Here - UWOMJ

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Here - UWOMJ

The University of Western Ontario Medical Journal
Volume 81, Issue 2, Fall 2012
www.uwomj.com
EDITORIAL
The Wonders of the Gastrointestinal Tract
Melissa J. MacPherson
5
FEATURE ARTICLES
Gastric Heterotopia in the Rectum: Progression of Disease
Michael Verbora
Faculty Reviewer: Dr. John Howard, MD, FRCP
6
Fight Against Obesity-Is Bariatric Surgery the Answer?
Chanseok (Chris) Rhee and Yuding Wang
Faculty Reviewer: Dr. Vladislav Khokhotva, MD, BSc, FRCSC
8
Fecal Microbiota Transplantation and Metagenomic Medicine
Arthur Ling
Faculty Reviewer: Dr. David Colby, MSc, MD, FRCPC
11
The Built Environment: How City Design Impacts Child Health
Chris Foster and Sophia Lane
Faculty Reviewer: Dr. Bryna Warshawsky, MD
14
ORIGINAL ARTICLES
Maladaptive Coping Behaviours of Medical Students
Derek Gateman, Julie Lebert, Alex Mee, Stephanie Spadotto, Piya Lahiry, Dr. Martyn Judson
Faculty Reviewer: Dr. Mark Speechley, BA, MA, PhD
16
GASTROENTEROLOGY ARTICLES
Radiofrequency Ablation (RFA) in the Treatment of Liver Tumours
Alden Ling, Brennan Ballantyne, Alexander Pazionis
Faculty Reviewer: Dr. Nirmal Kakani, MBBS, MRCS, FRCR
20
Colonoscopy in Screening and Diagnosis of Colorectal Cancer
Thomas Fear, Angela Zhang, Joshua Rosenblat
Faculty Reviewer: Dr. Nitin V. Khanna, MD, FRCPC
22
The Final Gift: Ethical and Legal Considerations of Liver Donation and Patient Selection
Jonathan Fairbairn, Niran Argintaru
Faculty Reviewer: Dr. Paul Marotta, MD, FRCPC
25
Biologic Agents in the Management of Inflammatory Bowel Disease: Is it worth it?
Tommy Choy, Jessica Jackson
Faculty Reviewer: Dr. John Howard, MD, FRCPC
28
Is it what you know or how you use it? A review of nutrition knowledge and counseling among medical professionals
Stephanie Gottheil, Charlotte Hunter
31
Acupuncture in the Treatment of Irritable Bowel Syndrome
Alexander Yan, Yin Hui, Caitlin VanDeCappelle
Faculty Reviewer: Dr. Larry Schmidt, MD, CCFP
34
UWOMJ | 81:2 | Fall 2012
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Volume 81, Issue 2, Fall 2012
www.uwomj.com
GASTROENTEROLOGY ARTICLES
The Use of Gene Expression Profiling in the Personalization of Colorectal Cancer Treatment
Laura Callan, Melissa J. MacPherson
Faculty Reviewer: Dr. Brian Dingle, MSc, MD, FRCPC
36
Gastroenterology Profiles: Dr. John Howard
Lauren Sham, Abdul Naeem, Joyce Zhang
39
Thinking Like an Emergency Doctor
Elaine Tang, Roman Shapiro, Kimberly Fielding
Faculty Reviewer: Dr. Naveem Poonai, MSc, MD, FAAP, FRCPC
41
A Case of Adult Intussusception: A Curious Presentation
Yikang Lin, Stephen Cornish
Faculty Reviewer: Dr. Patrick Colquhoun, MD
43
Helicobacter pylori: hiding in the modern miasma
Justine Denomme, Jason L. Chan
Faculty Reviewer: Dr. Carole Creuzenet, PhD
45
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UWOMJ | 81:2 | Fall 2012
EDITORIAL TEAM
EXECUTIVE TEAM
EDITOR-IN-CHIEF
PENCILLA LANG (MD/PHD 2014)
SENIOR ASSOCIATE EDITORS
JOYCE T.W. CHEUNG (MEDS 2013)
PAUL KUDLOW (MEDS 2013)
JUNIOR ASSOCIATE EDITOR
MELISSA J. MACPHERSON (MEDS 2014)
COPY EDITOR/BLOG
LAUREN SHAM (MEDS 2014)
JUNIOR FINANCIAL OFFICER
LAURA CALLAN (MEDS 2015)
LAYOUT EDITOR
JOYCE ZHANG (MEDS 2015)
IT/EXTERNAL OFFICER WINDSOR
ABDUL NAEEM (MEDS 2014)
IT
MAYOORENDRA RAVICHANDIRAN (MEDS 2013)
DEPARTMENTAL EDITORS
CLINICAL PROCEDURES
BRENNAN BALLANTYNE (MEDS 2014), ALDEN LING (MEDS 2014), ALEXANDER PAZIONIS (MEDS 2015)
DIAGNOSTIC REVIEW
JOSHUA ROSENBLAT (MEDS 2014), THOMAS FEAR (MEDS 2014), ANGELA ZHANG (MD/PHD 2018)
ETHICS AND LAW
NIRAN ARGINTARU (MEDS 2014), JONATHAN FAIRBAIRN (MEDS 2014)
HEALTH POLICY AND ECONOMICS
JESSICA JACKSON (MEDS 2015), TOMMY CHOY (MEDS 2015)
HEALTH PROMOTION
STEPHANIE GOTTHEIL (MEDS 2014), CHARLOTTE HUNTER (MEDS 2015)
INTERDISCIPLINARY
CAITLIN VAN DE CAPPELLE (MEDS 2014), ALEXANDER YAN (MEDS 2015), YIN HUI (MEDS 2015)
MEDICINE AND TECHNOLOGY
MELISSA J. MACPHERSON (MEDS 2014), LAURA CALLAN (MEDS 2015)
PROFILES
LAUREN SHAM (MEDS 2014), ABDUL NAEEM (MEDS 2014), JOYCE ZHANG (MEDS 2015)
THINKING ON YOUR FEET
ROMAN SHAPIRO (MEDS 2014), KIMBERLY FIELDING (MEDS 2014), ELAINE TANG (MEDS 2015)
ZEBRA FILES
YIKANG (KANGRUI) LIN (MEDS 2014), STEPHEN CORNISH (MEDS 2015)
HISTORY OF MEDICINE
JASON CHAN (MD/PHD 2017), JUSTINE DENOMME (MEDS 2015)
EDITORIAL BOARD
DR. LOIS CHAMPION
DR. FAISAL REHMAN
DR. MICHAEL RIEDER
DR. JIM SILCOX
DR. JEFFREY NISKER
DR. DOUGLAS QUAN
COVER ART: ASHLEY KIM
FRONT: The gastrointestinal system illustrates the elegant coordination and co-dependence of several vital structures that work together to
aid in digestion (Media: Pen and Ink, October 2012).
UWOMJ | 81:2 | Fall 2012
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UWOMJ | 81:2 | Fall 2012
EDITORIAL
The wonders of the gastrointestinal tract
Melissa J. MacPherson, PhD (Meds 2014)
T
he human gastrointestinal (GI) tract is an impressive 9 m long,1
extending from gums to bum. Its surface area is an astounding
4500 m2 all packed neatly into the thoracic and abdominal cavities of the human body!1 It comprises an incredibly complex set of organs including the esophagus, stomach, liver, gall bladder, pancreas, intestines, and colon. It is the site of digestion, nutrient absorption, waste
excretion and the primary site of metabolism. Without the GI tract, our
bodies couldn’t function. It’s no wonder that the field of gastroenterology is enormous. Unfortunately, our current UWOMJ issue provides
only a small snapshot of its breadth. One of its recurring themes is the
use of technology in the treatment and diagnosis of disease, which several of our departments have chosen to highlight. As you read these pages,
you will learn about radiofrequency ablation in the treatment of liver
tumours and colonoscopy in the screening and diagnosis of colorectal
cancers.
REFERENCES
1. The human digestive tract. Encyclopedia Brittanica [internet]. [cited 2012 Oct
20] Available from: http://www.britannica.com/ EBchecked/topic/1081754/
human-digestive-system
Other authors have chosen to highlight specific diseases and their
management. You will read about a curious presentation of adult intussusception and the use of acupuncture in the management of irritable
bowel syndrome. Michael Verbora discusses the progression of a rare
case of gastric heterotopia in the rectum. Arthur Ling has written an
interesting article outlining the use of fecal microbiota transplantation
and metagenomics in gastroenterology.
A number of other articles are also not to be missed. Niran Argintaru
and Jonathan Fairbairn from our department of ethics and law have written a thought provoking piece regarding the ethical and legal complexities of liver organ donation. The department of health promotion discusses the importance of nutritional knowledge and counseling among
medical professionals. The history of medicine department has written
an intringuing article on the discovery of the causative agent of duodenal ulcers and the reluctance of the medical profession to embrace the
hypothesis of an infectious cause.
In every issue of the UWOMJ we interview a local physician or scientist. In this edition we had the privilege of interviewing Dr. John
Howard, a pediatric gastroenterologist who also teaches us during our GI
curriculum. The profiles article detailing his career is not to be missed.
I hope that you enjoy this issue of the UWOMJ and learn a bit more
about the GI system as we take an adventure together down the gastrointestinal tract!
UWOMJ | 81:2 | Fall 2012
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FEATURE ARTICLE
Gastric heterotopia in the rectum: progression of
disease
Michael Verbora (Meds 2013)
Faculty Reviewer: Dr. John Howard, MD, FRCP (Department of Medicine and Pediatrics)
G
astric heterotopia is a condition whereby gastric mucosa is discovered outside of its origin. Gastric heterotopia within the rectum is rather rare. To date less than 50 cases have been reported.1
To our knowledge, no cases have been reported in which there is a review of progression, or elimination, of disease over time. We describe a
case of a patient from age 5 to 24 and report on symptoms and effectiveness of several treatments for heterotopic gastric mucosa in the rectum.
A 5 year-old boy presented to the Emergency Department with rectal bleeding. He mentions a three-day history of constipation. He was
treated with a fleet enema and prescribed mineral oil and told to return
if further bleeding returned. A barium enema was negative at this time.
He eventually is referred to gastroenterology for further investigation
after complaining of rectal bleeding four years after his initial presentation.
On history, the 9-year-old boy mentions continued painless, bright
red bleeding per rectum (BRBPR) several times per month. Despite the
bleeding, he is currently plotting along the 60th percentile for height and
weight. Past medical history was significant for asthma and family history revealed rectal polyps in his father. A previous trial of metronidazole
did not improve his symptoms. Both a review of systems and physical
exam were unremarkable. A flexible sigmoidoscopy was performed in
clinic that day. A large multi-lobular sessile polyp was discovered just
inside the rectum and multiple biopsies were taken. Pathology from the
rectal lesion showed colonic mucosa with specialized gastric type mucosa. Glands were straight and lined by parietal and chief cells (gastric
mucosa markers) with no evidence of erosion or ulceration. Helicobacter pylori, a bacteria that causes peptic ulcer disease, was not present.
One month later, the boy was scheduled for colonoscopic fulguration
of the rectal heterotopia. An ovoid lesion approximately 5cm in length
and 3cm in width with gastric rugae was removed using electocautery.
Once again, pathology confirmed gastric type mucosa without H. pylori.
He was prescribed 20mg omeprazole, which resolved bleeding.
At age 17, he complains of similar episodes of BRBPR. He mentions
that episodes of constipation coincide with his episodes of rectal bleeding. A second 3x4cm lesion with gastric rugae was removed via argon
plasma coagulation.
He presents again at age 24 with several episodes of rectal bleeding.
He mentions that an over the counter weight loss supplement that he
began taking has improved the bleeding and increased his bowel movements to 3-4 times per day. On sigmoidoscopy nothing is visualized. He
was scheduled for repeat colonoscopy.
topic gastric mucosa has been discovered in all areas of the gastrointestinal tract.2 It is most commonly found within the esophagus. The
exact mechanism for the development of heterotopic gastric mucosa has
yet to be determined. A number of theories exist including, the abnormal regenerative process following destruction of normal mucosa or the
competing theory that an error of differentiation of pluripotent endoderm cells during embryonic development leads to heterotopic gastric
mucosa.3
Gastric heterotopia typically presents with painless bleeding; however, cases have been reported with more serious complications such
as major gastrointestinal bleeding, bowel perforation, megacolon, intussusception, perianal fistula and rectovesical fistula.3 H. pylori has also
been discovered as an active infection in gastric heterotopia in a case of
a 5 year-old boy.4 Infection can lead to ulceration and severe bleeding.
The definitive diagnosis occurs via analysis of the biopsied tissue.
Typically the pathology is that of fundic-type mucosa but, case reports
have reported lesions containing gastric body, pyloric, antral, chief, salivary and parietal cells within the tissue sample.5
Treatment at this point in time for gastric heterotopia lacks consistency and evidence. Some argue that the gastric mucosa has the potential
to become malignant, as has been discovered for heterotopic gastric mucosa in the esophagus, and thus should be excised.6 To date there are no
reports of a malignant gastric heterotopia within the rectum. Successful
treatments to suppress the bleeding include proton pump inhibitors or
H2 receptor blocker. Co-infection with Helicobacter pylori may warrant
triple therapy with antibiotics and proton pump inhibitors. Endoscopic
ablation has the advantage of removing the tissue permanently.
CONCLUSION
Gastric heterotopia is a rare cause of gastrointestinal bleeding from the
lower tract in children. Endoscopic evaluation with biopsy is fundamental to diagnosis. The type of tissue present in heterotopic gastric mucosa
can vary, as well as the presence of H. Pylori infection, but to date no
malignant lesions have been discovered in the rectum. Treatment varies
from proton pump inhibitors and monitoring or removal of the lesion
via endoscopy.
REFERENCES
1. Bernadette, M., & Wildemore, M. Gastric Heterotopia of the Rectum: A Case
Report. The Internet Journal of Pathology, 5. 2007
DISCUSSION
2. Kestemnberg, A., G, M., de Lima, E., FT, G., Carrascal, E., & JL, A. Gastric heterotopic mucosa in the restum with helicobacter pylori-like organism:
a rare cause of rectal bleeding. International Journal of Colorectal Disease,
1993 (8):9-12.
In pediatric studies, the ratio prevalence of gastric heterotopia in the
rectum is twice that for males with a mean age of 5 years old. Hetero-
3. Sauer, C. G., Bickson, S. J., & Borowitz, S. M. Gastric Heterotopia of the
Rectum. Journal of Pediatric Gastroenterology & Nutrition, 2009 50(3):329-
6
UWOMJ | 81:2 | Fall 2012
FEATURE ARTICLE
333.
4. Vincenzi, F., L, B., Bizzarri, B., Boccellari, F., Fornaroli, F., & de’Angelas,
G. (2010). Gastric heterotopia in rectum with helicobacter pylori active infection in a 5-year-old child. Case Report and review of pediatric literature.
XVII National Congreee SIGENP Abstracts/Digestive and Liver Diseases,
2010 (42S): S321-S376.
5. Steele, S., Mullenix, P., & Martin, M. Heterotopic Gastric mucosa of the anus:
a case report and review of the literature. Am Surg, 2004 (70):715-719.
6. Christensen, W., & Sternberg, S. Adenocariconma of the upper esophagus
arising in ectopic gastric mucosa. American Journal of Surgical Pathology,
1987 (11): 397-402.
UWOMJ | 81:2 | Fall 2012
7
FEATURE ARTICLE
Fight against obesity – is bariatric surgery the
answer?
Chanseok (Chris) Rhee (Meds 2013), Yuding Wang (Meds 2013)
Faculty Reviewer: Dr. Vladislav Khokhotva, MD, BSc, FRCSC (Department of Surgery, Windsor Regional
Hospital)
O
besity is a medical state in which an individual has excessive
body fat that causes an increased risk of metabolic derangement. It is conventionally defined as a body mass index (BMI)
of 30 kg/m2 or more.1 Although it may not be considered as a disease
by itself, it has been long associated with many diseases that are often
detrimental to health, such as coronary artery disease, stroke, diabetes,
osteoarthritis, obstructive sleep apnea and more. Consequently, obesity
leads to more functional limitations, decreased health-related quality of
life, and increased utilization of the healthcare system.2 Currently more
than half of Canadians are reported as overweight (BMI of 25 kg/m2 or
higher) or obese,3 with nearly a quarter of the population being obese.4
A more concerning feature is that this proportion has doubled between
1980s and today, and it is still increasing.4 A systemic review of articles
published between 1990 and 2009 showed that obesity accounts for approximately 0.7% to 2.8% of a country’s total healthcare expenditure5.
In addition, the average medical costs spent on an obese individual were
approximately 30% greater than the costs on an individual with normal
weight.5 In Canada where healthcare costs are universally covered, the
total healthcare costs for being overweight and obese were estimated to
be $6.0 billion, which is 4.1% of the total health expenditure in 2006.6
Although direct comparisons between countries are often difficult due
to different methodologies implemented in measuring associated medical costs, higher weight-associated healthcare expenditures in Canada
can be linked to a higher rate of overweight and obese individuals. In
Ontario, an obese individual lays an additional burden of about $180
to the healthcare system over one year compared to a normal-weight
individual adjusted for other health-related factors such as age, gender,
socioeconomic status, and physical activity status.7 In addition, obesity
is also associated with other factors that cannot be easily quantified in
monetary value but nevertheless impact one’s life, such as quality of life
and level of education.7
Considering the socioeconomic downfalls of obesity, the benefits of
weight loss are apparent both for individuals and society. As obesity
is closely associated with lifestyle factors such as poor dietary choices and sedentary lifestyle, the current management of obesity focuses
mainly on lifestyle intervention.8 Weight loss interventions also often
provide social and psychological supports for improved effectiveness.9
The Counterweight Programme, a weight loss programme in primary
care in the UK which provides dietary and physical exercise schemes
and also follow-ups, is estimated to cost approximately $370 per individual per year.10 This cost does not include many extra costs imposed
on individuals, such as additional food costs and the costs of fitness club
memberships.10 A study by Roux and colleagues included medical, nonmedical, and time per patient costs for weight loss programmes, and
estimated an individual cost of US$3,040 per year.11 Although lifestyle
interventions may still be cost-effective, they require long-term commitment in both time and energy, with often less-than-expected results.9
8
Several factors associated with attrition include decreased body image,
decreased mental health, lower social support, lower self-efficacy, patient’s higher weight loss expectation, and cost.12 As a result, lifestyle
modification is often combined with pharmacotherapy, such as orlistat,
sibutramine and rimonabant. Although effective in weight reduction, the
cost of intervention with anti-obesity medications per quality-adjusted
life-year (QALY) was estimated to be US$20,000.13 In addition, adverse
effects of medication and high rates of weight regain limit the use of
pharmacotherapy.13
Currently, the most effective treatment of obesity is bariatric surgery which results in 30% sustained weight loss, compared to 5-10%
weight loss with behavioural and pharmacological intervention.14 Three
commonly-performed procedures are laparoscopic adjustable gastric
banding (LAGB), laparoscopic sleeve gastrectomy (LSG), and Rouxen-Y gastric bypass (RYGB).15 LAGB is a restrictive procedure where
a hollow, flexible silicone band is placed distal to the gastroesophageal
junction, reducing the stomach capacity.16 This causes early satiety and
decreased food intake, consequently resulting in weight reduction.16
LSG involves resection of a large portion of stomach, thus also reducing the stomach capacity.15 This is often a first of a two-stage procedure,
where rerouting of the small intestine is performed to reduce calorie
absorption, especially the absorption of fat.16 RYGB is the most common procedure performed in North America, comprising 51% of the
total bariatric procedures.15 It is a combination of both restrictive and
malabsorptive procedures and involves creating a small pouch of stomach and rerouting the small intestine. The mid-portion of the jejunum
is dissected and the distal portion is anastomosed with the small gastric
pouch. The proximal small bowel, connected to the excluded portion of
the stomach, forms a biliopancreatic limb and is anastomosed with the
distal jejunum.16 A malabsorptive state from bariatric surgery results in
favourable metabolic effects superior to those achieved by lifestyle and
pharmacological intervention.17 Its more substantial and long-lasting
weight loss effects place bariatric surgery as an attractive method of
weight reduction.17
In Ontario bariatric surgery is currently indicated for patients with
BMI of 40 kg/m2 who are refractory to medical management, including lifestyle modifications, or individuals with BMI greater or equal to
35kg/m2 with a major obesity-related comorbidity such as hypertension,
diabetes, or obstructive sleep apnea.18 Currently, the only operative bariatric technique being insured in Ontario is the RYGB, although multiple
private clinics offer the LABG technique. Although randomized control
trials (RCT) comparing the efficacy of bariatric surgery with standard
medical management are few, they do point to a significant benefit of
surgical management to decrease morbidity and mortality.19, 20 The landmark Swedish Obese Subjects (SOS) study (a large prospective multicenter matched cohort study) showed a significant mortality benefit for
UWOMJ | 81:2 | Fall 2012
FEATURE ARTICLE
patients who received bariatric surgery compared to non-surgical conventional treatment. 21 Subsequent retrospective and prospective studies have also shown similar results.22 RCTs between RYGB and LABG
have shown the RYGB procedure to have increased weight loss, improved resolution of comorbidities, lower reoperation rates and better
patient satisfaction. However, LABG offers faster recovery time and a
slightly lower rate of perioperative mortality and operative morbidity.23
The economic benefit from a payor’s perspective show that the long
term (10 years to lifetime) cost-effectiveness of surgery compared to
non-surgery has been estimated to be US$1000-40,000 per QALY when
using an incremental cost-utility ratio.24 A recent systemic review and
analysis for the Canadian Agency for Drugs and Technologies in Health
(CADTH) estimated the cost of bariatric surgery from a health care payor’s perspective to be CND$8,000-10,000 per QALY over the lifetime
horizon in Canada when using an incremental cost-utility ratio.25 This
estimate represents clear cost benefit for surgery compared to medical
treatment alone. Furthermore, analysis within subgroups such as obese
type 2 diabetics incurs even greater health and economic benefits. Recent meta-analysis evaluating bariatric surgery in patients with diabetes
shows an incremental cost-utility ratio of US$7,000-10,000 per QALY
and appears to provide a clear health net benefits and cost savings over
non-surgical management.26 Moreover, from a payor’s perspective, bariatric surgery represents an upfront investment with subsequent savings
spread throughout the patient’s lifetime in terms of both direct and indirect costs. Cost analysis between common surgical techniques are lacking and at this time no clear cost benefit can be assigned to RYGB versus
LABG, although it is known that LABG when compared to RYGB offers shorter hospital stay and faster recovery time (measured as time to
return to work).23
Currently, Ontario performs approximately 2,000 bariatric procedures per year funded through the OHIP.27 There are estimated 300,000
Ontario residents that are believed to be in need of the procedure.27 Even
with recent funding to increase the number of bariatric procedures provided by OHIP, there is still a significant wait time for the procedure.
As clinicians, prevention through life-style modifications before obesity
sets in may yet offer the best results. Nevertheless, bariatric surgery has
clear benefits over conservative and pharmacological treatments, and
increased funding for bariatric surgery in addition to continued lifestyle
modifications may warrant maximum long-term cost savings to OHIP.
REFERENCES
1. World Health Organization. Obesity and overweight. Media Centre [web
page on the Internet]. World Health Organization; 2011. Available from:
http://www.who.int/mediacentre/factsheets/fs311/en/. Accessed May 5, 2012.
2. Dong H, Unosson M, Wressle E, Marcusson J. Health consequences associated with being overweight or obese: a Swedish population-based study of
85-year-olds. Journal of American Geriatric Society 2012;60:243-250.
3. Statistics Canada. Body mass index, overweight or obese, self-reported,
youth, by sex, provinces and territories. In: Summary Tables [web page on
the Internet]. Ottawa: Statistics Canada; 2011. Available from: http://www.
statcan.gc.ca/tables-tableaux/sum-som/l01/cst01/health84a-eng.htm.
Accessed May 5, 2012.
4. Statistics Canada. Adult obesity prevalence in Canada and the United States.
In: Health Fact Sheets [web page on the Internet]. Ottawa: Statistics Canada; 2011. Available from: http://www.statcan.gc.ca/pub/82-625-x/2011001/
article/11411-eng.htm. Accessed May 5, 2012.
7. Tarride J, Haq M, Taylor VH, Sharma AM, Nakhai-Pour HR, O’Reilly D, Xie
F, Dolovich L, Goeree R. Health status, hospitalization, day procedures, and
physician costs associated with body mass index (BMI) levels in Ontario,
Canada. ClinicoEconomics and Outcomes Research 2012;4:21-30.
8. Verhaeghe N, Maeseneer JD, Maes L, Heeringen CV, Annemans L. Effectiveness and cost-effectiveness of lifestyle interventions on physical activity and eating habits in persons with severe mental disorders: a systematic
review. International Journal of Behavioral Nutrition and Physical Activity
2012;8:28-39.
9. Greaves CJ, Sheppard KE, Abraham C, Hardeman W, Roden M, Evans PH,
Schwarz P, The IMAGE Study Group. Systematic review of reviews of intervention components associated with increased effectiveness in dietary and
physical activity interventions. BMC Public Health, 2011;11:119-130.
10.Loveman E, Frampton GK, Shepherd J, Picot J, Cooper K, Bryant J, Welch
K, Clegg A. The clinical effectiveness and cost-effectiveness of long-term
weight management schemes for adults: a systematic review. Health Technology Assessment 2011;15(2):1-198.
11.Roux L, Kuntz KM, Donaldson C, Goldie SJ. Economic evaluation of weight
loss interventions in overweight and obese women. Obesity 2006;14:1093106.
12.Moroshko I, Brennan L, O’Brien P. Predictors of dropout in weight loss interventions: a systematic review of the literature. Obesity Reviews 2011;12:912934.
13.Neovius M, Narbro K. Cost-effectiveness of pharmacological anti-obesity treatment: a systematic review. International Journal of Obesity
2008;32:1752-1763.
14.Sandoval D. Bariatric surgery; beyond restriction and malabsorption. International Journal of Obesity 2011;35:545-549.
15.Schroeder R, Garrison JM, Johnson MS. Treatment of adult obesity with bariatric surgery. American Family Physician 2011;84(7):805-814.
16.Quigley S, Colledge J, Mukherjee S, Patel K. Bariatric surgery: a review
of normal postoperative anatomy and complications. Clinical Radiology
2011;66:903-914.
17.Eldar S, Heneghan HM, Brethauer SA, Schauer PR. Bariatric surgery for
treatment of obesity. International Journal of Obesity 2011;35:S16-S21.
18.Senger E. Bariatric surgery guidelines in need of revision, experts argue.
CMAJ. 2011 Mar 8;183(4):E234. Epub 2011 Jan 31.
19.Campos GM, Rabl C, Peeva S, et al. Improvement in peripheral glucose uptake after gastric bypass surgery is observed only after substantial weight loss
has occurred and correlates with the magnitude of weight lost. J Gastrointest
Surg. 2010 Jan;14(1):15-23. Epub 2009 Oct 17.
20.Padwal R, Majumdar S, Klarenbach S, Birch D, et al. The Alberta populationbased prospective evaluation of the quality of life outcomes and economic
impact of bariatric surgery (APPLES) study: background, design and rationale. BMC Health Serv Res. 2010 Oct 8;10:284.
21.Sjöström L, Gummesson A, Sjöström C, et al. Effects of bariatric surgery
on cancer incidence in obese patients in Sweden (Swedish Obese Subjects
Study): a prospective, controlled intervention trial. Lancet Oncol. 2009
Jul;10(7):653-62. Epub 2009 Jun 24.
22.Padwal R, Klarenbach S, Wiebe N, Hazel M, et al. Bariatric surgery: a systematic review of the clinical and economic evidence. J Gen Intern Med. 2011
Oct;26(10):1183-94. Epub 2011 May 3.
23.Martin A, Klemensberg J, Klein L, Urbach D, Bell CM. Comparison of
public and private bariatric surgery services in Canada. Can J Surg. 2011
Jun;54(3):154-69.
5. Withrow D, Alter DA. Economic burden of obesity worldwide: a systematic
review of the direct costs of obesity. Obesity Reviews 2012;12:131-141.
24.Terranova L, Busetto L, Vestri A, Zappa MA. Bariatric surgery: cost-effectiveness and budget impact. Obes Surg. 2012 Apr;22(4):646-53.
6. Anis AH, Zhang W, Bansback N, Guh DP, Amarsi Z, Birmingham CL. Obesity and overweight in Canada: an updated cost-of-illness study. Obesity Reviews 2010;11:31-40.
25.Klarenback S, Padwal R, Wiebe N, Hazel M, et al. Canadian agency for drugs
and technologies in Health- Bariatric surgery for severe obesity: systemic review and economic evaluation. CADTH technology report. 2010 Sept; 129
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FEATURE ARTICLE
26.Kashyap S, Gatmaitan P, Brethauer S, Schauer P. Bariatric surgery for type
2 diabetes: Weighing the impact for obese patients .Cleve Clin J Med. 2010
July; 77(7): 468–476.
27.Rynor B. Concerns raised about Ontario’s new regime for bariatric surgery.
CMAJ. 2010 Feb 23;182(3):E153-4. Epub 2010 Jan 4.
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UWOMJ | 81:2 | Fall 2012
FEATURE ARTICLE
Fecal microbiota transplantation and metagenomic
medicine
Arthur Ling (Meds 2015)
Faculty Reviewer: Dr. David Colby, MSc, MD, FRCPC (Departments of Microbiology and Immunology, Medicine and School of Dentistry)
INTRODUCTION
Have you ever had a gut feeling that you were not alone? Before you get
up to lock the doors, consider that our gastrointestinal tract, in particular
the distal colon, is home to trillions of bacteria and other microorganisms collectively referred to as the microbiome. Fortunately, most of the
microbiota are not harmful, but instead provide physiological functions
such as digestion and immune system development. Importantly, the intestinal microbiome acts as a front line defense against potential pathogens entering our gut. An important clinical example that highlights this
is an infection by a bacterium called Clostridium difficile, which usually causes a diarrheal/colitis syndrome, but in some cases may progress
into a life-threatening pseudomembranous colitis or a colonic distension called toxic megacolon. Although healthy individuals are resistant
to the ingested spores, cases of C. difficile infection (CDI) are on the rise
because of antibiotic treatments that disrupt the protective microbiota.1
To compound this problem, there are reports of increased incidence and
mortality rates, metronidazole resistance, and the emergence of hypervirulent strains (e.g. BI/NAP1/PCR 027).1,2 This ‘epidemic’ has forced
us to critically evaluate how we manage CDI cases, especially taking
into consideration the inherent dilemma that antibiotic therapy itself is
causing this infection.
What can be done? The standard treatment includes discontinuation
of the inciting antibiotics and adding other antibiotics (metronidazole,
vancomycin). Other additional therapies now include oral bacteriotherapy/probiotics, toxin binders, vaccination, and even performing surgical
bowel resection.2–4 However, despite additional medical therapy, there
are some patients (15 - 35%) that continue to have chronic recurring
disease or a severe presentation.5 For these patients, there has been a
last ditch protocol that focuses on replacing the disrupted microbiome
through a procedure called fecal microbiota transplantation (FMT).
Although this procedure has been around for over 50 years, it is not a
mainstream practice even though it has been found to provide safe, relatively inexpensive, and rapid relief with potential long term protection.
This is likely due to disinterest from patients (the ‘yuck’ factor), physicians (‘natural’ approaches without good evidence tend to be presumptively dismissed), and researchers. In this article, I will provide a fresh
perspective of FMT and discuss how it is becoming an increasingly attractive option in light of our improved understanding of the colonic
microbiome.
MI CACA ES SU CACA
FMT works on the principle of taking the bacteria in a healthy donor’s
stools and introducing them into the patient’s colon in order to restore
a ‘healthy’ intestinal microbiota population. Historically, FMT has been
studied and performed in veterinary medicine to treat various disorders
in farm animals (transfaunation).2 The first instance of FMT in humans
was in 1958, when a team of physicians in Colorado successfully treated
four patients with pseudomembranous colitis.6 At the time, three of these
patients had severe life threatening post-operative colitis that was unresponsive to conventional treatments. In a final attempt, the physicians
pioneered the FMT procedure and the patients miraculously recovered
and were discharged after several days. It would be much later in 1978
when C. difficile was identified to be a cause of antibiotic-associated
diarrhea/colitis, which was then followed by the first report of a successful FMT in a CDI case in 1981.6,7 While FMT was originally performed
by a crude colonic retention enema of homogenized stool samples obtained from closely related or intimate donors, the procedure has been
refined through the 1990s. Nowadays, most studies use standardized donor screening and stool collection, cryoprotectant processing and freezer
storage, and instillation with a nasogastric/nasoduodenal tube or guided
infusion with a colonoscope or upper tract endoscope.2,8,9 However, the
basic engraftment principle applied in 1958 is so simple that there are
even published ‘do-it-yourself’ guidelines that rely on easily acquired
items (e.g. kitchen blender, enema bag) and a healthy friend.10
Today, the main indication for FMT is severe refractory CDI or
chronic disease with a history of recurrence and a failure of multiple antibiotic regimens. While the evidence is limited to case series and reports
of chronic CDI, recent systematic reviews have found an astounding
89-92% clinical resolution of the diarrheal syndrome in over 300 cases
reported in the literature.2,3,11 These numbers are encouraging, but only
recently has there been interest in conducting a randomized controlled
trial (FECAL trial, 2008 - ongoing).12
One possible objection to FMT is the concern for safety as there is
the possibility for transmitting infections during the procedure. This is
a valid concern for any attempt to administer foreign microbiota as evidenced in trials of Saccharomyces boulardii probiotic treatment in CDI
patients, which had rare reports of sepsis and fungemia.13 Surprisingly,
in a systematic review of 376 cases of FMT in cases of CDI and other indications, there has not been a report of a major adverse event including
transmitted infection.3 Still, the possibility has been taken into consideration by developing protocols such as extensive donor screening in order
to prevent transmission of enteric pathogens and provide reconstitution
of ‘healthy’ microbiota. 8,14
FMT TREATMENT FOR OTHER DISEASES
Ulcerative colitis (UC) and Crohn’s disease are both types of idiopathic
inflammatory bowel disease (IBD) that are possible candidates for FMT
treatment because of the possible pathophysiologic role of the colonic
bacteria. The first report of FMT in UC treatment was 1989 by Bennet
and Brinkmann, in which Bennet, who suffered from persistent UC, successfully treated himself.15 Another report near the same time used FMT
to treat a variety of non-CDI associated colitis syndromes with some
UWOMJ | 81:2 | Fall 2012
11
FEATURE ARTICLE
degree of success.16 In 2003, there was a landmark study on treating UC,
which documented a case series of six patients with chronic UC who
underwent FMT.17 All of the patients in the study went into remission
and at 1-13 years of follow-up, none of the patients had any evidence
of active disease, indicating that the FMT treatments were associated
with a lengthy remission period or possible cure. While the evidence
is far from definitive, it does support the idea that FMT can be used to
treat other diseases that involve the colonic microbiota. These diseases
might include chronic constipation, obesity, metabolic syndrome/insulin
insensitivity, irritable bowel syndrome, allergic disease, and potentially
indirect neuropsychiatric alterations.16–21
PERSONALIZED METAGENOMIC MEDICINE
A lack of rigorous testing and abundance of biased anecdotal reports
has made it difficult for FMT to become widely accepted. However, this
may begin to change because of insights drawn from recent microbiome
research. To start off, consider the question: what makes each person
unique? Of course, many would say that it is a combination of genetic, epigenetic, and environmental factors, but traditionally few would
consider the microbiome as a significant influence. Yet, while genetic
sequence variations between individuals comprise a miniscule fraction
of our genome, the differences in microbiota populations have been estimated to be as high as 50%.21 Moreover, the microbiome is easily amenable to change and is also believed to demonstrate dynamic alterations
with normal ageing, geography, and environmental changes.22–24
Within this spectrum of variation within the population, there is the
possibility that the microbiome may contribute to disease susceptibility. Although many studies have experimentally implicated a role of the
colonic microbiome in various diseases, there is a need for population
based studies to establish an association between different microbiota
populations and specific diseases. To accomplish this, we can take advantage of next generation sequencing (NGS) technologies. Already
this year, there are several sequencing platforms (e.g. Nanopore, MiSeq,
Ion PGM-proton) touted to be able to provide extremely rapid and costeffective genetic sequencing capability. Using NGS, we can realistically
envision mapping out the human metagenome, which comprises all of
the microorganism genomes within the microbiome. Currently, there are
various initiatives supported by the International Human Microbiome
Consortium (IHMC) including the NIH Human Microbiome Project
(HMP) and the European Metagenomics of the Human Intestinal Tract
project (MetaHIT), which will perform metagenomic sequencing of
hundreds of individuals.25 One of the ground-breaking results has been
the classification (like blood typing) of individual intestinal microbiomes into 3 major ‘enterotypes’.22 In addition, at the recent IHMC congress, there were presentations showing metagenome-wide association
with both metabolic syndrome and type 2 diabetes.21 Although much
of the work is in the early stages, the future of personalized medicine
may someday involve individual metagenomes used as a pertinent factor in diagnosis, disease management, and determinants of health. In
this scenario, FMT could be used to treat people with disease-associated
microbiomes.
While FMT began as a last ditch therapy for pseudomembranous
colitis and CDI, our increasing understanding of the microbiome may
mean that FMT has a role in treating other diseases. History has shown a
lack of interest in FMT, but the anticipation from metagenomic research
and the urgency of the CDI epidemic may be the much needed push for
new advances. On an optimistic note, Kahn and colleagues report that
patients with UC are in favour of moving forward with FMT, suggesting that patients may not be as adverse to the idea as what we might
think.26 With any luck, we may see substantial developments in the years
to come.
12
REFERENCES
1. Heinlen, L. & Ballard, J.D. Clostridium difficile Infection. Am J Med Sci.
2010;340(3):247-252.
2. Brandt, L.J. & Reddy, S.S. Fecal Microbiota Transplantation for Recurrent
Clostridium difficile Infection. J Clin Gastroenterol. 2011;45(Suppl):159-167.
3. Borody, T.J. & Khoruts, A. Fecal microbiota transplantation and emerging
applications. Nature reviews. Gastroenterology & Hepatology. 2011;9(2):8896.
4. Borody, T.J. & Campbell, J. Fecal microbiota transplantation: current status
and future directions. Expert Review of Gastroenterology & Hepatology.
2011;5(6):653-655.
5. Mcdonald, L.C., Owings, M. & Jernigan, D.B. Clostridium difficile Infection
in Patients Discharged from US Short-stay Hospitals , 1996 – 2003. Emerg
Infect Dis. 2006;12(3):409-15.
6. Bartlett JG, Chang TW, Gurwith M, Gorbach SL, O.A. Antibiotic-associated
pseudomembranous colitis due to toxin-producing clostridia. N Engl J Med.
1978;298(10):531-4.
7. Bowden TA, Mansberger AR, L.L. Pseudomembranous enterocolits: mechanism of restoring floral homeostasis. Am Surg. 1981;47178-183.
8. Hamilton, M.J., Weingarden, A.R., Sadowsky, M.J. & Khoruts, A. Standardized Frozen Preparation for Transplantation of Fecal Microbiota for Recurrent Clostridium difficile Infection. Am J Gastroenterol. 2012;107(5):761-7.
9. Garborg, K., Waagsbø, B., Stallemo, A., Matre, J. & Sundøy, A. Results of
faecal donor instillation therapy for recurrent Clostridium difficile-associated
diarrhoea. Scand J Infect Dis. 2010;42(11-12):857-61.
10.Silverman, M.S., Davis, I. & Pillai, D.R. Success of self-administered home
fecal transplantation for chronic Clostridium difficile infection. Clin Gastroenterol Hepatol. 2010;8(5):471-3.
11.Gough, E., Shaikh, H. & Manges, A.R. Systematic review of intestinal microbiota transplantation (fecal bacteriotherapy) for recurrent Clostridium
difficile infection. Clinical infectious diseases : an official publication of the
Infectious Diseases Society of America. 2011;53(10):994-1002.
12.Nood, E.V., Speelman, P., Kuijper, E.J. & Keller, J.J. Struggling with recurrent Clostridium difficile infections: is donor feces the solution? Euro Surveill. 2009;14(34):pii=19316.
13.Maroo, S. & Lamont, J.T. Recurrent clostridium difficile. Gastroenterology.
2006;130(4):1311-6.
14.Cohen, S.H. et al. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the society for healthcare epidemiology of
America (SHEA) and the infectious diseases society of America (IDSA). Infect Control Hosp Epidemiol. 2010;31(5):431-55.
15.Bennet JD, B.M. Treatment of ulcerative colitis by implantation of normal
colonic flora. Lancet. 1989;1(8630):164.
16.Borody TJ, George L, A.P. et al. Bowel-flora alteration: a potential cure for
inflammatory bowel disease and irritable bowel syndrome? Med J Aust.
1989;150(10):604.
17.Borody, T.J., Warren, E.F., Leis, S., Surace, R. & Ashman, O. Treatment
of Ulcerative Colitis Using Fecal Bacteriotherapy. J Clin Gastroenterol.
2003;37(1):42-47.
18.Andrews PJ, B.T. “Putting back the bugs”: bacterial treatment relieves
chronic constipation and symptoms of irritable bowel syndrome. Med J Aust.
1993;159(9):633-4.
19.Fetissov, S.O. & Déchelotte, P. The new link between gut-brain axis and neuropsychiatric disorders. Curr Opin Clin Nutr Metab Care. 2011;14(5):477-82.
20.Vrieze, a et al. The environment within: how gut microbiota may influence
metabolism and body composition. Diabetologia. 2010;53(4):606-13.
21.Yong, E. Microbiome sequencing offers hope for diagnostics [Internet]. Nature News. 2012 Mar 23 [cited 2012 May 21]. Available from: http://www.nature.com/news/microbiome-sequencing-offers-hope-for-diagnostics-1.10299
UWOMJ | 81:2 | Fall 2012
FEATURE ARTICLE
.
22.Arumugam, M. et al. Enterotypes of the human gut microbiome. Nature.
2011;473(7346):174-80.
23.Yatsunenko, T. et al. Human gut microbiome viewed across age and geography. Nature. 2012;486(7402):222-7.
24.Mai, V., Ukhanova, M. & Baer, D.J. Understanding the Extent and Sources of
Variation in Gut Microbiota Studies; a Prerequisite for Establishing Associations with Disease. Diversity. 2010;2(9):1085-1096.
25.Lepage, P. et al. A metagenomic insight into our gut’s microbiome. Gut. 2012;
doi:10.1136
26.Kahn, S., Gorawara-Bhat, R. & Rubin, D.T. Fecal bacteriotherapy for ulcerative colitis: Patients are ready, are we? Inflammatory Bowel Diseases.
2012;18(4):676-684.
UWOMJ | 81:2 | Fall 2012
13
FEATURE ARTICLE
The built environment: how city design impacts
child health
Chris Foster (Meds 2014), Sophia Lane (Meds 2013)
Faculty Reviewer: Dr. Bryna Warshawsky, MDCM, FRCPC, Associate Medical Officer of Health for the Middlesex-London Health Unit
ABSTRACT
Environmental factors, such as soil, air and water quality, are well
known to influence population health. With the increasing urbanization of Canada and other countries around the world, more attention is
now being paid to how the ‘built environment’ – all the elements of the
environment designed by humans – also plays a crucial role in human
health. This article briefly examines how a few key components of the
built environment contribute to child health. Thoughtful placement of
schools and efforts to create safe, walkable neighbourhoods can increase
the number of students who walk to school instead of relying on cars.
Providing children and their families with recreational infrastructure
promotes physical activity. Creating farmers’ markets in urban cores increases access to a less expensive source of nutritious food for a city’s
inhabitants. Knowledge about these interactions between urban design
and child health can allow physicians to provide more practical advice to
their patients about developing a healthy lifestyle within a city. It is also
a promising field for physician advocacy: by offering their expertise to
inform city planning decisions and persuading city planners to consider
the health impacts of their decisions, physicians can help make it easier
for their young patients to live a healthy, active lifestyle.
THE BUILT ENVIRONMENT AND URBANIZATION
When considering individual patients, we are taught to consider the impact of patients’ environments on their health: where and with whom
they live, what kind of work they do, etc. It stands to reason that factors
of a larger environment – such as a neighbourhood or city – may influence the health of groups of people living there. Of specific interest is
the built environment (BE) – all of the elements of the environment
designed by humans –including the land-use zoning of a neighbourhood,
road layouts, access to shops and facilities, and the presence or absence
of sidewalks. A growing body of research illustrates that BE design in
urban and suburban areas can have a significant impact on the health of
people living in these areas. This article endeavours to give a practical
overview of the influence of BE on health, with a specific focus on how
BE can influence child health, activity levels and development.
Where people live in Canada has changed dramatically since World War
II and the subsequent boom of industry, with an increased proportion
of the population moving toward urban areas. Currently, 68% of the
Canadian population lives in metropolitan areas and this figure continues to increase annually.1 The development of sufficient housing and
infrastructure for the rapidly growing number of city dwellers often results in urban sprawl. The low-density housing and partitioned land use
common to suburban areas may now be contributing to chronic health
problems.2 At least four main threats of sprawl to population health have
been identified: physical inactivity, poor air quality, more motor vehicle
collisions due to reliance on cars, and mental health issues.3 Mitigating
14
such health effects requires an understanding of the interplay of city
design and human health followed by appropriate urban planning.
THE CURRENT STATE OF CHILD HEALTH IN CANADA
The most recent estimates suggest that 26% of Canadian children are
overweight and 8% are obese. The percentages of children that are overweight or obese have doubled and tripled, respectively, over the past 25
years and research indicates that these unhealthy body weights often
persist into adulthood.4 To curb this trend, public education has focused
on the importance of children eating five or more daily servings of fruits
and vegetables and engaging in regular physical activity. However, the
role of a child’s neighbourhood environment in influencing their physical activity and overall health is often not considered. Finding ways to
create an environment that encourages physical activity is a novel, population-based approach to help curb the trend toward childhood overweight/obesity as well as the presence of ‘adult’ diseases in children
(e.g., type 2 diabetes mellitus).
COMMUNITY PLANNING FOR HEALTHY LIFESTYLES
The School Commute
Walking to school was previously a staple daily activity for most children. However, this has been eroded by a trend toward building larger
centralized schools to which children must be bused, increased parental
fears over child safety and the construction of less ‘walkable’ neighbourhoods. Not surprisingly, the most important factor influencing whether
or not children commute to school in a physically active way is proximity. Specifically, if children live ≤ 800 m from their school they are 5-10
times more likely to commute actively to school than if they live farther
away.5
More subtle factors have also been identified that make a neighbourhood
‘walkable,’ namely what we associate with ‘older’ neighbourhoods – a
grid system layout with lots of connections between roads, high population density and a variety of land uses including housing, shops, services, and recreational facilities. Conversely, most suburban housing
developments are designed in such a way that walking is unappealing:
streets are often convoluted in their layout, connections to stores and
restaurants are limited, and there is a low population-density. These caroriented neighbourhoods discourage physically active transport.5 On the
contrary, children and adolescents who live in ‘walkable’ neighbourhoods not only walk to school more often but are also more likely to be
physically active outside of school hours.5
Both the real and perceived danger of a neighbourhood are critical factors in parents’ decisions about allowing their children to walk to school
and other local destinations. Similarly, older adolescents – especially
girls – are more likely to be active in their neighbourhoods if they perceive them to be safe.5 This may explain why males are more likely
UWOMJ | 81:2 | Fall 2012
FEATURE ARTICLE
to actively commute to school than girls – they tend to perceive their
neighbourhoods as safer. Creating safe neighbourhoods in which residents perceive them as such is key to encouraging physical activity.6
Recreational Facilities
The availability of recreational facilities (parks, playing fields, pools,
etc.) also plays a role in how active children are in a given environment.
A survey study done in London, Ontario found that after controlling
for season and demographic factors, youth who have two or more recreational facilities in their neighbourhood engage in an average of 17
minutes more daily physical activity than their comparable peers who
have fewer local facilities.7 Trails for walking and cycling can also help
to promote physical activity. One Texas study found a 1.5 times greater
odds of walking for a minimum of half an hour at least once a week
among people who perceived themselves as living close to a trail.8 This
is a modest finding, but does show a potential role of trails as one small
step in establishing a culture of physical activity for families. To maximize trail usage, city planners designing trail routes should note that trail
segments with mixed views of urban and natural landscapes as opposed
to only natural views experienced 39% higher trail traffic.8 This further
touts the health benefits of mixed land use mentioned in the studies on
walkable neighbourhoods.5
Access to Nutritious Food
Much like recreational opportunities, access to a source of nutritious
food can have a positive impact on a child’s health. Unfortunately, disparities in food access related to socio-economic factors have been well
documented in several studies in both the US and UK.9 Recent studies
have examined whether neighbourhood characteristics such as proximity to a grocery store serve to lessen such disparity. One Toronto study
found that only 1% of variation in food security and even less of the
variation in severe food insecurity could be attributed to one’s neighbourhood of residence. This effect actually disappeared completely after
accounting for covariates such as income, number of dependent children
and status as a recent immigrant, leading the researchers to conclude
“we found no evidence that geographic food accessibility mitigates the
effect of financial constraints on household food security.”9
Conversely, a different study examined the effects that the creation of
a farmer’s market in a food desert – a district with little or no access to
healthy foods – in London, Ontario had on the price and availability of
healthy food. The researchers found that the market improved access to
fresh foods such as broccoli and green grapes and allowed for hundreds
of dollars in potential annual savings for families.10 Such savings could
help to reduce the financial barriers to a healthy diet like those noted in
the Toronto study, allowing parents to afford healthier foods for their
children.
WHY SHOULD PHYSICIANS CARE?
Similarly to how overweight/obese children become overweight/obese
adults, physically active teens are much more likely to be active as
adults.11 By taking steps to ensure that our children and adolescent patients are active and healthy in their younger years we are setting the
foundation for healthy living in the years to come.
Preventing or delaying chronic disease in our children is one of the
most efficient ways to help both our community’s health and our overburdened health care system. Interventions to change the BE may serve
as a powerful tool in achieving this goal. Notably, changing the BE is
less reliant on evoking specific behavioural changes within individual
patients – a difficult task to which any doctor can attest. As Dr. Leonard Syme, an epidemiologist at UC Berkeley’s School of Public Health
points out, “Changing individual behaviours in isolation may be more
difficult than modifying the environment that facilitates and promotes
them”.2
WHERE DO WE GO FROM HERE?
For doctors to successfully harness urban planning as a new tool in patient care, there are two vital goals:
1.
collaboration with other professionals such as politicians, city planners, public health professionals and teachers
2.
advocacy for population health as a major factor in city planning
decisions
For example, physicians could join with school board officials and other
community partners in creating walk-to-school campaigns. This might
involve having pamphlets and other literature available in their offices
for parents, as well as speaking to their young patients about how walking to school can help keep them healthy. City planning advocacy could
follow the lead of the campaign that banned smoking in public places, in
which physicians played a crucial role. Hopefully as physicians become
more informed about the impact urban design can have on their patients,
similar advocacy gains can be made in the field of city planning.
REFERENCES
3. Census Snapshot of Canada - Urbanization [Internet]. Ottawa (ON): Statistics
Canada, Government of Canada; 2008 Nov 21 [cited 2012 May 1]. Available
from: http://www.statcan.gc.ca/pub/11-008-x/2007004/10313-eng.htm.
4. Johnson S, Marko J. Designing healthy places: Land use planning and public
health. Environments Journal [Internet]. 2008 [cited 2012 May 1]; 35(3):919. Available from: http://www.environmentsjournal.ca/index.php/ejis/article/view/10026/6977
5. Urban sprawl and health [Internet]. Edmonton (AB): Alberta Health Services,
Government of Alberta; 2009 Apr [cited 2012 May 1]. Available from: http://
www.albertahealthservices.ca/poph/hi-poph-hpp-info-urban-sprawl.pdf.
6. Canadian Community Health Survey [Internet]. Ottawa (ON): Health Canada, Government of Canada; 2006 Sep 26 [cited 2012 May 1]. Available from:
http://www.hc-sc.gc.ca/fn-an/surveill/nutrition/commun/cchs_guide_escceng.php.
7. Giles-Corti B, Kelty SF, Zubrick SR, Villanueva KP. Encouraging walking
for transport and physical activity in children and adolescents: how important
is the built environment?. Sports Med. 2009;39(12):995-1009.
8. Larsen K, Gilliland J, Hess P, Tucker P, Irwin J, He M. The influence of the
physical environment and sociodemographic characteristics on children’s
mode of travel to and from school. Am J Public Health. 2009 Mar;99(3):5206.
9. Tucker P, Irwin JD, Gilliland J, He M, Larsen K, Hess P. Environmental influences on physical activity levels in youth. Health Place. 2009 Mar;15(1):35763.
10.Starnes HA, Troped PJ, Klenosky DB, Doehring AM. Trails and physical activity: a review. J Phys Act Health. 2011 Nov;8(8):1160-74.
11.Kirkpatrick SI, Tarasuk V. Assessing the relevance of neighbourhood characteristics to the household food security of low-income Toronto families.
Public Health Nutr. 2010 Jul;13(7):1139-48.
12.Larsen K, Gilliland J. A farmers’ market in a food desert: Evaluating impacts on the price and availability of healthy food. Health Place. 2009
Dec;15(4):1158-62.
13.Pluhar ZF, Piko BF, Uzzoli A, Page RM, Dull A. Representations of the relationship among physical activity, health and perceived living environment in
Hungarian urban children’s images. Landscape Urban Plan. 2010;95(4):151160.
UWOMJ | 81:2 | Fall 2012
15
ORIGINAL ARTICLE
Maladaptive coping behaviours of medical students
Derek Gateman (Meds 2013), Julie Lebert (Meds 2013), Alex Mee (Meds 2013), Stephanie Spadotto (Meds
2013), Piya Lahiry (Meds 2013), and Dr. Martyn Judson
Faculty Reviewer: Dr. Mark Speechley, BA MA PhD (Epidemiology & Biostatistics, UWO)
ABSTRACT
Background/Context: Medical school, and particularly clerkship, is
stressful. Little research exists regarding the use of substances and potentially addictive behaviours to cope with medical school stressors.
Such coping strategies present an ethical issue as they may hinder academic or clinical performance.
Objective: To compare the use of five maladaptive coping behaviours –
caffeine, alcohol, gambling, tobacco, and drugs – between pre-clerkship
and clerkship students.
Methods: A cross-sectional study was performed using an anonymous
online survey distributed to all medical students at the Schulich School
of Medicine & Dentistry. Data was analysed using Student t-tests to
compare the mean number of coping behaviours used. Subgroup analyses using Mid-P Exact chi-squared tests were conducted to examine the
prevalence of each.
Results: The total number of maladaptive behaviours was not statistically different between the pre-clerkship and clerkship years. Subgroup
analyses indicated no significant differences in the use of any one behaviour, while there were trends towards significance in the prevalence of
non-prescription drug use.
Conclusion: The study lacked statistical power to show an increase in
the total use of maladaptive coping behaviours between pre-clerkship
and clerkship students. There were also no significant changes in the
use of any specific behaviour. Future studies would benefit from a larger
sample size and longitudinal study design.
INTRODUCTION
In health literature, the term ‘stress’ signifies a negative experience produced from the interaction between the person and his or her environment, resulting in psychological, physical and behavioural consequences.1-4 According to the American Psychological Association (APA), stress
has become a growing concern because of its physical and psychological
consequences.5 People employ various coping strategies in an attempt to
manage stress. Coping can be defined as behavioural efforts employed
to manage, reduce, or control stress.6 In a 2009 survey performed by
APA, 81% of those surveyed believed they were managing their stress
well; however, many of them were using maladaptive strategies such as
tobacco, gambling, or drinking alcohol as coping mechanisms.6
Several studies worldwide have demonstrated that being in medical
school is one of the most stressful experiences due to the volume of information, long hours of study, and limited time for self and/or family.7
Moreover, the clerkship period is particularly stressful since the students
transition from didactic-based learning to direct patient care.8 Overall,
these stressors can cause a detrimental effect on academic performance,
16
physical health, and psychological well-being, ultimately influencing
performance, not only as students, but also later as caregivers.9, 10 Despite the potential importance of coping strategies, few investigators
have studied how physicians cope with stress. Of these, most report
positive coping behaviours, such as seeking counselling, meditation,
and exercising.7, 11 However, no recent literature has reported maladaptive coping behaviours as a way to manage stress as a medical student.
It was hypothesized that there would be an increase in use of potentially
addictive behaviours as coping mechanisms in medical school from preclerkship to the clerkship years. Specifically, the presence and prevalence of the following maladaptive behaviours were examined: caffeine,
alcohol, gambling, tobacco, and non-prescription drug use. The aim of
this study is to provide a deeper understanding of the maladaptive coping mechanisms that medical students use.
METHODS
Medical students from the classes of 2014, 2013, 2012, and 2011 at the
Schulich School of Medicine & Dentistry were asked, via electronicmail, to complete an online survey of their use of caffeine, alcohol, gambling, tobacco, and drugs. Participation in this study was voluntary and
anonymous. This study was approved by the Schulich research ethics
board (REB consent #17613E).
For each of the five maladaptive behaviours, the participant was
asked to i) report the frequency of use in the last six months, ii) gauge
his or her dependence on each coping mechanism. As well, questions
regarding whether the student felt those coping mechanisms had ever
influenced their performance in social, academic, or professional situations were included. The data were collected in January 2011, which
gave first year clerks an opportunity to experience the stressors of clerkship for five months before responding.
A cross-sectional analysis of the 242 respondents was conducted
with students divided into pre-clerkship (2014 and 2013) and clerkship
(2012 and 2011) years. Since all survey data were de-identified, only
group analyses were conducted. The differences between the total number of maladaptive coping mechanisms employed by pre-clerkship and
clerkship students were compared and analysed using two-tailed Student
t-tests. In addition, subgroup analyses were performed using two-tailed
Mid-P Exact chi-squared tests to identify differences between pre-clerkship and clerkship groups with respect to the prevalence of each.
RESULTS AND DISCUSSION
Numerous studies have discussed the stresses and pressure that students
face during their medical training.12, 13 Several have also suggested that
clerkship is particularly stressful for students.8 Most studies of the methods used by medical students to cope with these stresses have focused on
engagement and disengagement or active and avoidance mechanisms.7,
UWOMJ | 81:2 | Fall 2012
ORIGINAL ARTICLE
Table 1. Subgroup analyses of the five maladaptive behaviours in Pre-Clerkship and Clerkship Students.
Pre-Clerkship (%)[SD]
Clerkship (%)[SD]
P-value
N=149
N=93
Male
71 (47.7)
37 (39.8)
0.231
108 (44.6)
Female
78 (52.3)
56 (60.2)
0.231
134 (55.4)
Used in last 6 months
141 (94.6)
90 (96.8)
0.645
231 (95.4)
Mean weekly1
7.67 [6.68]
9.96 [7.82]
Dependence
53 (37.6)
33 (36.7)
86 (37.3)
Coping
91 (64.5)
44 (48.9)
135 (55.8)
141 (94.6)
86 (92.5)
Mean weekly
4.20 [3.97]
3.80 [4.77]
Dependence
2 (1.4)
0 (0)
2 (0.9)
Coping
21 (14.9)
23 (26.7)
44 (19.4)
Influence on performance
43 (30.5)
20 (23.2)
63 (27.8)
26 (17.4)
14 (15.1)
1.60 [3.82]
1.32 [1.56]
Dependence
0 (0.0)
0 (0.0)
0 (0.0)
Coping
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
13 (8.7)
14 (15.1)
0.31 [0.86]
1.01 [2.14]
Dependence
1 (7.7)
2 (14.3)
3 (11.1)
Coping
2 (15.4)
4 (28.6)
6 (22.2)
29 (19.5)
28 (30.1)
0.89 [1.79]
1.41 [2.05]
Dependence
1 (3.6)
1 (3.6)
2 (3.6)
Coping
5 (17.2)
4 (14.3)
9 (15.8)
Total (%)
N=242
Gender
Caffeine
Alcohol
1
0.509
227 (93.8)
Gambling
Mean monthly1 dose
0.636
40 (16.5)
Tobacco
Mean monthly dose
1
0.139
27 (11.2)
Drugs
Mean monthly dose
1
0.062
57 (23.6)
7 (24.1)
7 (25.0)
14 (24.6)
Mean use of each behaviour reported weekly or monthly excluding responses where survey participants denied use within the last 6 months. Values
reported as: mean [standard deviation].
1
This study is one of the first to directly examine the use of substances
and potentially addictive behaviours as methods of coping with stress.
Specifically, we examined the use of caffeine, gambling, tobacco, and
drug use in medical students across the four years of Schulich School of
Medicine and Dentistry (Table 1).
14
The total prevalence of maladaptive coping behaviours (caffeine,
gambling, tobacco, and drug use) in the clerkship years and the preclerkship years was not significantly different (P=0.227) with reported
average number of inappropriate strategies used of 2.49 and 2.35, respectively. While this did not support the hypothesis, it may be secondary to the small sample size. The prevalence of these behaviours is displayed by group in Figure 1. Over 80% of the students reported the use
UWOMJ | 81:2 | Fall 2012
17
ORIGINAL ARTICLE
Figure 1. Bar graph showing number of maladaptive coping behaviours in pre-clerkship and clerkship students. The total number of the five coping
mechanisms –caffeine, alcohol, gambling, tobacco and drugs (x-axis) – with frequency of use in percent (y-axis) is depicted as bar graphs for the preclerkship and clerkship groups.
of two or three maladaptive behaviours. The most commonly reported
studies, more than one Canadian medical school should be enrolled to
behaviour was caffeine use (95.4%), followed by alcohol use (93.8%).
achieve a greater number of participants. In addition, this study was a
Interestingly, 23.6% of medical students reported the use of drugs in the
cross-sectional study of a group of pre-clerkship and clerkship students,
past six months. Additionally, 27.8% of students who reported alcohol
rather than a longitudinal study of the same class during the transition to
use and 24.6% of students who reported drug use also indicated that
clerkship. Unlike a longitudinal study, any differences observed could
it has had a negative influence on their performance or attendance at
be a blend of cohort effects and true changes in the outcomes over time.
school or in the clinic and/or hospital setting.
These preliminary results should be further explored using a longitudinal study to follow the same cohort of medical students through their
Subgroup analyses were performed for each coping mechanism
pre-clerkship and clerkship years.
looking at prevalence. The frequency of use, dependence, use of the
behaviour to cope with stress, and influence on performance are preWhile there was no significant difference found between the presented in Table 1 for interest, but not statistical analysis. In subgroup
clerkship and clerkship groups, all of the survey respondents were medianalysis, no statistical difference was found between the clerkship and
cal students, and as such were exposed to the stress of medical educapre-clerkship groups. However, there is a trend towards significance in
tion in general. A similar study of students in other professional degree
the prevalence of non-prescription drug use (P=0.062). This suggests
programs or post-secondary education may be prudent; this would allow
there may be a greater amount of drug use in the clerkship years as a
for examination of the effect of exposure to medical school stresses on
coping strategy. Since the survey defined drugs to be ‘mood-altering
coping, without the distinction of exposure to clerkship. Further study
substances’ as well as ‘pharmaceuticals used not as directed’, it would
might be complicated by the difficulties of assigning an appropriately
be of interest to investigate the specific drugs that are being consumed
matched cohort. For example, medical students are typically older than
in order to better categorize the level and type of dependence. Specifistudents enrolled in other undergraduate programs.
cally, future study may differentiate illicit drugs like marijuana, cocaine,
In conclusion, this study did not find significant differences in the avand heroin from the unintended use of Gravol for sleep induction, which
erage number of maladaptive coping behaviours used by pre-clerkship
have very different social perceptions.
and clerkship medical students. Further analysis likewise did not demAlthough this is a novel study looking at the students of one Canaonstrate significant differences in the prevalence of caffeine, alcohol,
dian medical school and their maladaptive behaviours, it does have two
gambling, tobacco, and non-prescription drug use as a coping strategy.
main drawbacks: the sample size and the type of study. The sample size
There were, however, trends towards significance in the greater use of
of this study was limited to the 242 medical students who completed the
non-prescription drugs by clerkship students. This study cannot convoluntary survey. Consequently, this study has many trends towards sigclude that the elevated stress of clerkship years in medical school is
nificance, yet only a few statistically significant observations. For future
correlated with maladaptive behaviours. Consequently, these results
18
UWOMJ | 81:2 | Fall 2012
ORIGINAL ARTICLE
illustrate the need for further study, focussing particularly on the use
of non-prescription drugs. Future study may benefit from longitudinal
design and greater sample size, as well as the inclusion of non-medical
students. With more information, it may be valuable to consider implementing programs to help students cope with stress in a more productive
and positive manner.
cal Book Co.; 1983.
7. Mosley TH, Perrin SG, Neral SM, Dubbert PM, Grothues CA, Pinto BM.
Stress, coping, and well-being among third-year medical students. Acad Med.
1994; 69(9): 765-7.
DISCLOSURE
8. Santen SA, Holt DB, Kemp JD, Hemphill RR. Burnout in medical students:
examining the prevalence and associated factors. South Med J. 2010; 103(8):
758-63.
The authors declare that no conflicting interests exist and that no direct
or indirect funding was received to conduct this study.
9. Holm M, Tyssen R, Stordal KI, Haver B. Self-development groups reduce
medical school stress: a controlled intervention study. BMC Med Educ. 2010;
10: 23.
REFERENCES
1. Aldwin CM. Stress, coping, and development: an integrative perspective.
New York : Guilford Press; 2007.
2. Clark S, Cooper C. The risk management of occupational stress. Health, Risk
and Society. 2000 2(2): 173-87.
3. Cummings TG, Cooper CL. Cybernetic framework for studying occupational
stress. Human Relations. 1979; 32: 395-418.
4. Quick JC, Quick JD. Organizational stress and preventative management.
New York:McGraw-Hill; 1984.
5. Rizzolo D, Sedrak M. Stress management: helping patients to find effective
coping strategies. Jaapa. 2010; 23(9): 20-4.
6. Scheiber SC, Doyle BB. The impaired physician. New York : Plenum Medi-
10.Stewart SM, Betson C, Marshall IB, Wong CM, Lee PW, Lam TH. Stress and
vulnerability in medical students. Med Educ. 1995; 29(2): 119-27.
11.Redhwan, AAN, Sami AR, Karim AJ, Chan R, Zaleha MI. Stress and coping
strategies among management and science university students: a qualitative
study. The International Medical Journal. 2009; 8(2): 11-6.
12.Dyrbye LN, Thomas MR, Shanafelt, TD. Systemic review of depression anxiety, and other indicators of psychological distress among US and Canadian
medical students. Acad Med. 2006; 81(4): 354-73.
13.Firth J. Levels and sources of stress in medical students. Br Med J (Clin Res
Ed). 1986; 292(6529): 1177-80.
14.Stewart SM, Betson C, Lam TH, Marshall IB, Lee PW, Wong CM. Predicting
stress in first year medical students: a longitudinal study. Med Educ. 1997;
31(3): 163-8.
UWOMJ | 81:2 | Fall 2012
19
CLINICAL PROCEDURES
Radiofrequency ablation (RFA) in the treatment of
liver tumours
Alden Ling (Meds 2014), Brennan Ballantyne (Meds 2014), and Alexander Pazionis (Meds 2015)
Faculty Reviewer: Dr. Nirmal Kakani MBBS MRCS FRCR (Department of Radiology)
BACKGROUND AND HISTORY
needles as well as poses a risk of complications resulting in surgery.8
The incidence of primary liver cancer in Canada has been steadily increasing, having more than doubled since 1980.1 This increase is partially attributed to the increasing rates of hepatitis C infection, alcohol
abuse, and immigration from developing countries where the incidence
of hepatocellular carcinoma (HCC) is much greater.1,2 The liver is also
the most common site of metastases, especially from colorectal cancers.3
The best treatment option for HCC and liver-only metastases is surgical
resection, however, only 10-15% of patients are suitable candidates for
this procedure.4 As such a small proportion of patients are eligible for
surgical resection or able to receive a liver for transplantation, a number
of different modalities have been explored as treatment options, including, but not limited to, radiofrequency ablation (RFA), radiotherapy, percutaneous ethanol injection, and transarterial chemoembolization. RFA
is safe, and associated with fewer side-effects and shorter hospital stays
compared to surgical resection.5
RADIOFREQUENCY ABLATION
The use of heat in medicine dates back to antiquity when various
ancient societies from the Greeks to the Chinese knew of the use of cautery to stop bleeding. In 1891, Jacques-Arsene d’Arsonoval found that
alternating current at 20kHz or higher can heat tissue in the human body
without muscle excitation.6 Nearly four decades later, Harvey Cushing
and William T Bovie developed the Bovie knife, a small knife where an
alternating current was passed so that it can burn through or cauterize
the tissue on contact.7 In the early 1990’s radiofrequency electrocautery
was further explored, and modified into what is now RFA as a way of
treating small liver tumours.6
EVALUATION AND CONTRAINDICATIONS
Prior to operation, the nature of the liver tumours are carefully evaluated
by abdominal CT or MR imaging. Tumours larger than 5cm or numbering greater than five are contraindications for treatment by RFA due to
the difficulty in ablating a tumour of such a size.4 Their location relative
to pertinent structures such as other visceral organs, bile ducts and vessels are noted as it complicates the procedure. It is difficult to completely
ablate tumours near vessels due to the cooling effect of the blood flow.
Ablation also poses a risk for causing necrotic damage to nearby organs
such as the bowel or diaphragm, as well as causing biliary obstruction
and damage. Although the majority of RFA in the liver are performed on
primary HCC tumours or colorectal metastases, it is also performed on
metastases from other areas such as the pancreas and breast. Despite the
advantages presented by RFA, surgical resection is still considered the
gold standard, and should be considered if the patient is found to be eligible on evaluation. However, this is rapidly changing as more advanced
RFA techniques emerge. Extra-hepatic involvement is also a relative
contraindication for RFA. Hematology tests for coagulopathies are performed as the procedure may require multiple insertions of large gauge
20
There are three primary approaches to performing an RFA: percutaneous, laparoscopic, and open. Percutaneous RFA is above all the preferred
approach as it is the least invasive, requires only conscious sedation,
inexpensive, has minimal side effects, and the patient can be discharged
within 24 hours. Earlier percutaneous procedures were limited to those
with a few small tumours in the periphery and away from the diaphragm.
However, with advanced techniques such as hydrodissection these challenging lesions can also be treated. Advanced ultrasound and 3D ultrasound, coupled with CT scanning has helped to visualise the entire liver
to help in abalation.9
There are only a few centres where interventional radiology is not
available that perform laparoscopic RFA, and this is usually used in conjuction with liver resection, or other debulking surgeries. This approach
is generally used on patients with centrally located tumours, tumours
located near large blood vessels, and those with minimal abdominal
procedures performed in the past. As it is a more invasive approach, it
is less cost-effective, associated with more complications, and requires
a longer hospital stay. It is also much more technically challenging to
perform, as the angle of approach of the radiofrequency needle is restricted.10
The open approach is generally reserved for those patients with multiple large tumours ranging from 4-5cm or involves a large vessel. An
open approach allows for the temporary occlusion of the hepatic artery
and portal vein, known as a Pringle maneuver, which minimizes blood
flow. As the cooling effect from the blood flow is minimized, the larger
tumours are more likely to be completely ablated. If the patient also
presents with a separate tumour that cannot undergo RFA but is suitable
to be resected, it can be surgically removed during the same operation.
The disadvantages of this approach are similar to those of other open
surgeries as it is more expensive, requires general anesthesia, a longer
hospital stay and is associated with increased morbidity and mortality.4
Prior to the operation, the site of entry is locally anesthetized and
the patient is given an IV sedative. General anesthesia is indicated for
percutaneous RFA when poor tolerance is expected with local anesthetic
alone as in cases of drug abuse or cancer patients, or if the operation is
expected to last more than 3 hours.8
The RFA needle is guided towards the tumour by ultrasonography.
The aim of the procedure is to ablate the entirety of the tumour as well
as a 1-2cm tumour-free margin.11 However, ultrasounography is unable
to accurately show the extent of the ablation, and tumour margins tend
to be obscured by the ablative action, so care must be taken to ensure
complete ablation.12 Tumours are usually treated from the deepest to the
UWOMJ | 81:2 | Fall 2012
CLINICAL PROCEDURES
most superficial as the ablated area may obscure ultrasonographic visualization of deeper tissue. Single ablations are usually suitable for small
tumours smaller than 3cm, but for larger tumours, multiple overlapping
ablations should be considered. The RFA needle remains active during
removal from the tumour to prevent seeding of malignant tissue along
healthy liver tissue. Post-operatively patient is given an antiemetic and
analgesics to control the nausea and pain often associated with RFA.8
4. Curley SA, Izzo F, Delrio P, Ellis LM, Granchi J, Vallone P, Fiore F, Pignata
S, Daniele B, Cremona F. Radiofrequency ablation of unresectable primary
and metastatic hepatic malignancies: results in 123 patients. Ann Surg. 1999
Jul;230(1):1-8.
POST-OP AND COMPLICATIONS
6. McGahan JP, Dodd G. Radiofrequency ablation of the liver: current status.
AJR. Am J Roentgenol. 2001;176:3-16.
An abdominal CT is performed one month after the operation to assess the extent of the tumour ablation. A waiting period is necessary as
ablation causes a temporary hyperemic ring to appear on CT that may
obscure any remaining tumour areas. After this a repeat CT is performed
routinely to look for possible intra or extrahepatic tumour recurrence. If
an intrahepatic tumour recurrence is found, the patient can undergo percutaneous RFA again. Percutaneous RFA can be repeated as many times
as necessary in contrast to the other RFA approaches which are often
one-time procedures. If the recurrence is large or complicated, then other treatment modalities may be considered such as chemoembolization.8
A portion of patients may experience flu-like symptoms 3-5 days
post-operation that is also described in patients of similar procedures
such as chemoembolization and cryoablation. The fever may be accompanied by fatigue and night sweats lasting anywhere from 1-3 weeks.
Supportive care is recommended, but if the fever lasts longer than 5
days, the patient is assessed for possible sepsis. RFA is generally considered safe, but some serious complications have been reported such as
pleural effusions, intraperitoneal bleeding, and burns to the diaphragm
and colon.8
FUTURE DIRECTIONS
5. Salhab M, Canelo R. An overview of evidence-based management of hepatocellular carcinoma: a meta-analysis. J Cancer Res Ther. 2011 OctDec;7(4):463-75.
7. Ray CE, Hicks ME, Patel NH, et al. Interventions in Oncology. Fairfax, Va:
Society of Interventional Technology; 2003:181-194.
8. Dodd GD, Lees WR, Lee FT. Minimally invasive treatment of malignant hepatic tumours. Radiology 1999;213(P):58
9. Curley SA. Radiofrequency ablation of malignant liver tumours. Ann Surg
Oncol. 2003 May;10(4):338-47. Review.
10.Siperstein AE, Rogers SJ, Hansen PD, Gitomirsky A. Laparoscopic thermal
ablation of hepatic neuroendocrine tumour metastases. Surgery 1997;122 :
1147-1155
11.Cady B, Jenkins RL, Steele GD Jr, et al. Surgical margin in hepatic resection
for colorectal metastasis: a critical and improvable determinant of outcome.
Ann Surg 1998;227:566 -571
12.Gurney JM, Lee FT Jr, Cha C, Markhardt BK, Mahvi DM, Warner TF. CT
vs ultrasound (US) for guidance of radiofrequency (RF) ablation in a porcine liver model: radiologic-pathologic correlation (abstr). Radiology
1999;213(P):123
13.Goldberg SN, Stein MC, Gazelle GS, Sheiman RG, Kruskal JB, Clouse ME.
Percutaneous radiofrequency tissue ablation: optimization of pulsed-radiofrequency technique to increase coagulation necrosis. J Vasc Interv Radiol
1999;10:907 -91
A major hurdle in RFA is the difficulty in fully ablating large tumours.
Currently, a single ablation can reach a tissue volume 2-3cm in diameter, but multiple ablations in the same area or reducing hepatic vascular inflow can increase the effective ablated volume. Newer and more
effective needles and radiofrequency generators have been developed
since the advent of RFA to increase ablation volume and further improvements continue to be researched. One such innovation being investigated is the use of pulsed current RFA as opposed to constant current
RFA where the former was found to produce a larger volume of tissue
necrosis.13 Other energy sources such as Microwave technology are also
being used for ablation.
The benefits of the minimally-invasive nature of percutaneous RFA
are obvious in the treatment of small tumours in early stage HCC. However, in a situation where a patient would be suitable for both RFA and
surgical resection, the latter would be the standard of care, but very few
patients are candidates for surgical resection due to pre-existing complex liver disease. If a large randomized control trial can show that best
curative treatment between RFA, surgical resection, and liver transplantation in early HCC is RFA, then it may become the new standard of care
due to its cost-effectiveness and minimal complications.
REFERENCES
1. Canadian Cancer Society’s Steering Committee on Cancer Statistics. Canadian Cancer Statistics 2011. Toronto, ON: Canadian Cancer Society; 2011.
2. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA
Cancer J Clin. 2005 Mar-Apr;55(2):74-108.
3. Lewandowski RJ, Thurston KG, Goin JE, Wong CY, Gates VL, Van Buskirk
M, Geschwind JF, Salem R. 90Y microsphere (TheraSphere) treatment for
unresectable colorectal cancer metastases of the liver: response to treatment
at targeted doses of 135-150 Gy as measured by [18F]fluorodeoxyglucose
positron emission tomography and computed tomographic imaging. J Vasc
Interv Radiol. 2005 Dec;16(11):1641-51.
UWOMJ | 81:2 | Fall 2012
21
DIAGNOSTIC REVIEW
Colonoscopy in screening and diagnosis of
colorectal cancer
Thomas Fear (Meds 2015), Angela Zhang (MD/PhD 2018), Joshua Rosenblat (Meds 2014)
Faculty Reviewer: Dr. Nitin V. Khanna, MD, FRCPC (Department of Medicine, Division of Gastroenterology)
INTRODUCTION
Colonoscopy is an endoscopic tool used for the visualization and biopsy
of the large intestine with important applications in the investigation of
colorectal cancers. Colonoscopy has been used to diagnose colorectal
cancer since the late nineteen sixties, and is currently the gold standard.
However, colonoscopy is not without shortcomings and attempts have
been made to improve this technique. This paper will briefly review the
history of colonoscopy, its current applications, and the limitations of
colonoscopy for the diagnosis and screening of colon cancer. It will
lastly examine innovations in colonoscopy and the advantages they
might offer.
HISTORY OF COLONOSCOPY
Dr. William Wolff, and Dr. Hiromi Shinya, pioneered the development
of the colonoscope.1 Their invention, in 1969, was an advance over the
barium enema and the flexible sigmoidoscope because it allowed for the
visualization and removal of polyps from the entire large intestine.1, 2
Wolff and Shinya advocated for their invention and published much of
the early evidence needed to overcome skepticism about the device’s
safety and efficacy.2 Once the basic technology of the colonoscope had
been accepted, the device lent itself to adaptations that have bettered its
performance, and broadened its applications. The use of colonoscopy
to screen and diagnose colorectal cancer continues to rise.1, 4, 5 Ultimately, the significance of the test has been to permit an understanding of
colorectal cancer through the collection of biopsies, and to lower mortality through screening and diagnosis.6, 7
COLORECTAL CANCER AND COLONOSCOPY: CURRENT
INDICATIONS
Colorectal cancer is the second most common cause of death from cancer among both Canadian men and women; an estimated 22 000 cases
were diagnosed in 2011.8 Most colon cancers begin as small protruding
growths called polyps. The chance that a polyp will develop into cancer
varies from 2% in lesions under 1.5 cm in diameter to approximately
10% in lesions over 2.5 cm in diameter. 9 Premalignant polyps are estimated to progress over a period of approximately 10 years.10 Early forms
of colorectal cancer are amenable to treatment. If the disease is detected
in a local stage, the 5 year survival rate is 90 percent.6 However, if the
cancer has spread regionally the survival rate is 68%, and if disease has
metastasized the survival rate is only 10%.6 Unfortunately, most cases
of colon cancer are asymptomatic until advanced stages of the disease.11
Given the long progression time of this form of cancer and the high
success rate of early treatment, it is not surprising that screening programs for colorectal cancer have been able to show substantial survival
benefits.6 Colonoscopy has played an important role in these programs.
The current guidelines on the screening of colorectal cancer ac-
22
knowledge that a wide range of acceptable options exist. For individuals of average risk over 50 years of age, the recommendation is
colonoscopy every ten years, flexible sigmoidoscopy (FISG) every five
years, or annual fecal occult blood testing (FOBT).6 Colonoscopy is the
recommended screening test for most individuals with increased risk
for colorectal cancers.6 Additionally, colonoscopy is the recommended
follow-up procedure for positive FOBT and FSIG.
As a screening test, colonoscopy has two distinct advantages compared to other means of screening for colorectal cancer. One advantage
is that it can be used to remove polyps from the entire length of the
colon, which reduces the incidence of colorectal cancer.6, 9 Furthermore,
colonoscopy provides biopsy samples which screen for patients that are
at a higher risk of developing cancers in the future; these patients will
benefit from more frequent screening.6, 12
LIMITATIONS OF COLONOSCOPY
While colon cancer is a serious disease, the lifetime prevalence is approximately 6% in North America; 94% of patients who are screened
with colonoscopy do not benefit from undergoing the procedure. 11
Therefore, despite the obvious potential for colonoscopy to prevent
colorectal cancer, it is necessary to examine the discomfort and risk that
patients are exposed to, the limitations in sensitivity, and the costs of
colonoscopy.
Patients undergoing colonoscopy require moderate sedation and dietary bowel preparation.11 The preparation involves consuming a fluid
diet and Pico-Salax, a mix of osmotically active and laxative substances.
Not all patients manage to complete the entire preparation as required
and this can decrease test sensitivity as polyps may be missed in stool. 13
In addition, the test is uncomfortable and patients require mild sedation
at the minimum. Despite sedation, the test is perceived negatively.14
As a consequence, compliance has substantially hindered the effectiveness of colonoscopy based screening programs.15 Furthermore, a general
anesthetic is often required for patients who feel too much pain or discomfort on mild sedation alone. This substantially increases the cost.11
As well as discomfort to the patient, undergoing colonoscopy also
carries the risk of complication. The most severe complications, bowel
perforation and bleeding, are estimated to occur approximately 1.64 and
0.85 times, respectively, per thousand tests.16 The rate of complication
has also been reported to rise substantially following polypectomy, to
approximately 8 per one thousand tests.17
When evaluating the test performance of standard colonoscopy, polyps are estimated to be missed at a rate of 27% overall and 6% for adenomas larger than 1 cm.18 Colonic cancer is also reported to be missed at
a rate of 5% with standard colonoscopy.18 However, there is substantial
variation in test characteristics based on the operator.19
UWOMJ | 81:2 | Fall 2012
DIAGNOSTIC REVIEW
From a health care system perspective, colonoscopy has significant facility and equipment costs and requires technical expertise to be performed effectively. In Canada, it is estimated to cost $352 per diagnostic
procedure, or $467 per therapeutic procedure, when overhead costs and
the physician’s fee are included in the estimate. 20
The limitations of colonoscopy must be considered in the context of
the primary alternatives. FSIG is an endoscopic technique done with
minimal bowel preparation and without sedation. However, FSIG only
allows the only distal third of the large bowel to be visualized, making
it less sensitive than colonoscopy.6 The FOBT is a less invasive, test for
the finding of occult blood in the stool, which is suggestive of colorectal cancers and large polyps. However, the FOBT is significantly less
sensitive and specific than colonoscopy. Also, the test characteristics of
FOBT vary significantly depending on the brand, collection technique,
and number of samples taken per test.6
Although imperfect, colonoscopy does offer improved sensitivity
compared to other tests. And while the invasiveness, cost, and risk of
complication are frustrating drawbacks, they have not obscured its importance in the screening and diagnosis of colorectal cancers. Rather,
they have spurred innovation aimed at modifying standard colonoscopy
to address its limitations.
ADVANCED TECHNIQUES
Virtual Colonoscopy
REFERENCES
1. Wolff IW. Colonoscopy: History and development. Am J Gastroenterol. 1989
Sep;84 (9):1017-25.
2. Wolff IW, Shinya H. Earlier diagnosis of cancer of the colon through colonic
endoscopy (colonoscopy). 1974 Sep;34 (S3); 912-931.
3. Wolff IW, Shinya H. Colonofiberoscopic Management of Colonic Polyps.
1973 Mar-Apr;16(2):87-93.
4. Westwood DA, Alexakis N, Connor SJ. Transparent cap-assisted colonoscopy versus standard adult colonoscopy: a systematic review and meta-analysis.
Dis Colon Rectum. 2012 Feb; 55(2):218-25.
5. Zapka J, Klabunde CN, Taplin S, Yuan G, Ransohoff D, Kobrin S. Screening
Colonoscopy in the US: Attitudes and Practices of Primary Care Physicians.
J Gen Intern Med. 2012 Apr 27. [Epub ahead of print]
6. Levin B, Lieberman DA, McFarland B, et al. Screening and surveillance
for the early detection of colorectal cancer and adenomatous polyps, 2008:
a joint guideline from the American Cancer Society, the US Multi-Society
Task Force on Colorectal Cancer, and the American College of Radiology.
Gastroenterology. 2008; 134:1570-1595.
7. Wolff IW, Shinya H. Morphology, anatomic distribution and cancer potential
of colonic polyps. Ann Surg. 1979 December; 190(6): 679–683.
8. Colorectal cancer statistics at a glance [Internet]. Toronto (On): 2012 Canadian Cancer Society; [updated 2012 May 1; cited 2012 May 4]. Available
from: http://www.cancer.ca/canada-wide/about%20cancer/cancer%20statistics/stats%20at%20a%20glance/colorectal%20cancer.aspx#ixzz1eXlqNK7g
A less invasive alternative to traditional colonoscopy is virtual colonoscopy, also known as CT colonography. A helical CT image is used
to create a computer generated 3-dimentional model of the colon. The
model can then be visualized digitally for the presence of polyps.19 CTcolonography is non-invasive, does not require sedation, and avoids major risks such as bleeding and perforations.21 However, in the event of
a polyp being detected a standard colonoscopy is still required for its
removal. As with standard colonoscopy, bowel preparation is required
and the result depends upon the operator’s skill in the interpretation of
the results.21 A possible risk of screening with CT- colonography is that
the radiation exposure might promote new cancers – a published estimate is a 0.14% risk.19 Though few centres are equipped to carry out
the procedure, recent guidelines have endorsed it as sufficient screening once every five years for average risk individuals.19, 6 Currently, CTcolonography is mostly used in the situation of a technically difficult
colonoscopy (excessive colonic looping) or diverticulosis, and may be
advantageous to increase compliance in patients who cannot tolerate
standard colonoscopy.21, 19
9. Mayer RJ. Chapter 91. Gastrointestinal Tract Cancer. In: Longo DL, Fauci
AS, Kasper DL, Hauser SL, Jameson JL, Loscalzo J, eds. Harrison’s Principles of Internal Medicine. 18th ed. New York: McGraw-Hill; 2012. http://
www.accessmedicine.com/content.aspx?aID=9115982. Accessed May 4,
2012.
Capsule Endoscopy
14.Harewood GC, Wiersema MJ, Melton III LJ. A prospective, controlled assessment of factors influencing acceptance of screening colonoscopy. The
American Journal of Gastroenterology. 2002 Dec; 97(12); 3186–94.
Similar to CT-colonography, capsule endoscopy aims to avoid the invasiveness of traditional colonoscopy. In capsule endoscopy, a small pill
equipped with a camera is swallowed and passed through the bowel to
collect images.22 Capsule endoscopy does not allow for biopsy or operator steering, and still requires a dietary bowel preparation, but does not
require sedation.23 Though at present it is used in Europe, investigations
of the current technology indicate a lack of sensitivity to warrant replacing other screening test.24
CONCLUSION
Since its development, colonoscopy has been widely used to screen for
and diagnose colorectal cancers. However, because it is an invasive and
costly test that requires extensive preparation by the patient and technical expertise to be performed it is not ideal for this purpose. In response
to these limitations, several innovations have focused on less invasive
and more accurate means of screening and diagnosis to compliment
standard colonoscopy in the management of colorectal cancers.
10.Winawer SJ, Fletcher RH, Miller L, Godlee F, Stolar MH, Mulrow CD, Woolf
SH, Glick SH, Ganiats TG, Bond JH, Rosen L, Zapka JG, Olsen SJ, Giardiello FM, Sisk JE, Van Antwerp R, Brown–Davis C, Marciniak DA, Mayer RJ.
Colorectal Cancer Screening: Clinical Guidelines and Rationale. Gastroenterology. 1997;112:594–642.
11.Cappell, MS. Reducing the Incidence and Mortality of Colon Cancer: Mass
Screening and Colonoscopic Polypectomy. Gastroenterology Clinics. 2008
Feb;37(1);129-160
12.Bretthauer M, Kalager M. Colonoscopy as a Triage Screening Test. N Engl J
Med. 2012 Feb; 366:759-760.
13.Hookey LC, Vanner SJ. Pico-salax plus two-day bisacodyl is superior to picosalax alone or oral sodium phosphate for colon cleansing before colonoscopy.
Am J Gastroenterol. 2009 Mar; 104(4); 703-709.
15.Lieberman DA. Cost-effectiveness model for colon cancer screening. Gastroenterology. 1995 Dec; 109(6); 1781–1790.
16.Rabeneck L, Paszat LF, Hilsden RJ, Saskin R, Leddin D, Grunfeld Eva, Wai
E, Goldwasser M, Sutradhar R, Stukel TA. Bleeding and Perforation After
Outpatient Colonoscopy and Their Risk Factors in Usual Clinical Practice.
Gastroenterology. Dec 2008; 135(6);1899-1906.
17.Levin TR, Zhao W, Conell C, Seeff LC, Manninen DL, Shapiro JA, Schulman J. Complications of Colonoscopy in an Integrated Health Care Delivery
System. Annals of Internal Medicine. 2006 Dec; 145(12);880-886.
18.Rex DK, Cutler CS, Lemmel GT, Rahmani EY, Clark DW, Helper DJ, Lehman GA, Mark DG Colonoscopic miss rates of adenomas determined by backto-back colonoscopies. Gastroenterology. Jan 1997. 112(1):24-28.
19.Mandel, JS. Screening for Colorectal Cancer. Gastroenterology Clinics. 2008
Feb; 37(1);97-115.
UWOMJ | 81:2 | Fall 2012
23
DIAGNOSTIC REVIEW
20.Sharara N, Adam V, Crott R, Barkun AN. The costs of colonoscopy in a
Canadian hospital using a microcosting approach. Can J Gastroenterol. June
2008;22(6):565-570.
21.Johnson CD, Chen M, Toledano AY, Heiken JP, Dachman A,Kuo MD, Menias
CO, Siewert B, Cheema JI, Obregon RG, Fidler JL, Zimmerman P, Horton
KM, Coakley K, Iyer RB, Hara AK, Halvorsen Jr. RA, Casola G, Yee J,
Herman BA, Burgart LJ, Limburg PJ. Accuracy of CT Colonography for Detection of Large Adenomas and Cancers. N Engl J Med. 2008 Sep. 359:12071217.
22.Van Gossum A, Munoz-Navas M, Fernandez-Urien I, Carretero C, Gay G,
Delvaux M, Lapalus MG, Ponchon T, Neuhaus H, Philipper M, Costamagna
G, Riccioni ME, Spada C, Petruzziello L, Fraser C, Postgate A, Fitzpatrick
A, Hagenmuller F, Keuchel M, Schoofs N, Devière J. Capsule Endoscopy
versus Colonoscopy for the Detection of Polyps and Cancer. N Engl J Med.
2009 July; 361:264-270.
23.Riccioni ME, Urgesi R, Cianci R, Bizzotto A, Spada C, Costamagna G. Colon
capsule endoscopy: Advantages, limitations and expectations. Which novelties? World J Gastrointest Endosc. 2012 Apr 16;4(4):99-107.
24.Bretthauer M. The Capsule and Colorectal-Cancer Screening — The Crux of
the Matter. N Engl J Med. 2009 July; 361:300-301.
24
UWOMJ | 81:2 | Fall 2012
ETHICS AND LAW
The final gift: ethical and legal considerations of
liver donation and patient selection
Jonathan Fairbairn (Meds 2014) and Niran Argintaru (Meds 2014)
Faculty Reviewer: Dr. Paul Marotta, MD, FRCPC (Department of Gastroenterology)
T
he first liver transplants were performed in 1963 on three patients,
with the longest surviving for 22 days.1 The ability to sustain
patients beyond the 25% one year survival seen throughout the
1970s was made possible by the introduction of a key immunosuppressant agent, cyclosporine A in the early 1980s.2 Living donor liver transplantation (LDLT), which involves a liver resection of the right liver
lobe in adults, and the left lobe in children was first performed in 1988
in a pediatric recipient and 1996 in an adult recipient.3 At press, 1,742
living and deceased donor liver transplants have been performed in London, Ontario.4
Liver transplantation is a life-saving procedure with the ability to
significantly decrease mortality and morbidity for high-need patients.
Procurement of organs for any type of transplantation is a major limiting factor and presents a significant challenge to their fair and equitable
distribution. Currently, there are 218 people waiting for a liver transplant
in Ontario.5 Patient selection, therefore, aims to maximize the benefits
of transplant while minimizing the risks associated with the procedure.
There are multiple ethical considerations applicable to patient selection and organ donation practices. Legislation governing organ and
tissue transplantation also play a central role in patient selection. Here
we explore some of these ethical and regulatory considerations of liver
transplants and the widening gap between demand and supply in Canada.
RECIPIENT SELECTION
Organ donation represents a “final gift” one can bestow on another individual. This sentiment imposes substantial responsibility on the medical system to select suitable recipients in an ethical and just manner. In
addition to numerous immunological and physiological considerations,
relevant social factors need to be considered when allocating a finite
resource for which there is such high demand. Should patients who require transplants as a result of their own actions, such as alcohol related
disease or IV drug use (Hepatitis B, Hepatitis C), be considered on equal
grounds with those requiring a liver transplant due to circumstances out
of their control?
Eunice Booker, the mother of an organ donor was quoted in The
Guardian as saying “I find it offensive that one in four livers donated
goes to alcoholics… [The liver should go to] the one who’s not an alcoholic, they are more entitled.”6 Further, the rate of alcoholic recidivism
post-transplantation is estimated at 11 to 22%.7 In addition, IV drug use
(IVDU) use is a significant cause of Hepatitis C, which is the most common indication for liver transplantation among adults. Retransplantation
for recurrent HCV infections is estimated at 3.6%-5.0%.8
Whether a patient is responsible for their past alcoholism or IVD
use poses the question of whether individuals that abuse substances are
exercising free will. If they are deemed not to be free agents, penalizing
them would be unfair. Many arguments could be raised on both sides
of the issue, including the strong genetic preponderance to alcoholism,
and the higher prevalence of comorbid psychiatric illnesses among substance abusers. In addition, the time elapsed between when the causative behavior has ceased and when transplantation is necessary may
be a significant duration, even decades. The legal system has tended
to believe those abusing substances should be held accountable. However, given the aims of the legal system are to uphold justice and apply
criminal punishments, while the medical system aims to allocate medical resources and heal, the role of free will in decision-making may not
be the same. Further, this can lead down a slippery slope: Do alcoholics
deserve a liver? Do smokers deserve a lung? Does a street-racer deserve
an ICU stay following a crash? 9
As medical innovations result in an increased number of chronically
ill and older patients being eligible for liver transplant, it is important
to consider the presence of comorbidities and the patient’s age. Thus,
should an elderly individual with multiple comorbidities be considered
on equal grounds with a young adult without any comorbidities, who
has the potential of a considerably longer lifespan and better outcomes?
Utilitarian ethics would favor donation to the younger and healthier patient. However, widespread application of this criterion would systematically exclude older and sicker patients from transplantation. Given
the moral obligation of providers to all patients, this would lead to an
unjust outcome.
The solution of Canadian transplant organizations to these issues is
a pragmatic one, which generally avoids passing moral judgments, and
circumvents adding qualifiers to the value of human life. The Model for
End-stage Liver Disease (MELD) is a scoring system used to estimate
disease severity. This model is widely implemented in the US, and increasingly in Canada.10 When an organ becomes available, recipients
are considered starting with the patient in greatest need and sequentially
going down the list, checking for compatibility between the donor and
potential recipient (including body size and blood type).11
In Ontario, the relevant human tissues legislation is the Trillium Gift
of Life Network (TGLN) Act. The Ontario waiting list is managed by
TGLN. The transplant organizations have protocols to communicate
with one another, and will cross-match medically urgent patients. When
an interprovincial donation occurs, transportation, even across Canada,
can be arranged in a matter of hours. However, in part due to the fragmented transplant network, organs are only occasionally donated outside a province. The system in Canada is in contrast to the U.S., which
has a national registry, known as the United Network for Organ Sharing
(UNOS).9
ORGAN DONATION AND SUPPLY
There are two sources for liver donations: living donors and cadaveric
UWOMJ | 81:2 | Fall 2012
25
ETHICS AND LAW
donors. Out of the 6,000 transplants performed in the United States annually, only 320 are living donor transplants.13 Donation after Cardiac
Death (DCD), or “non-beating heart donors”, are cadaveric donors who
donate following withdrawal of life support. While DCDs were performed many years ago in Canada, they were re-introduced after a national forum in 2005.14 The London Health Sciences Centre (LHSC), a
Canadian leader in the field, is the provincial leader, having transplanted
over 30 of the 100 DCDs performed in Ontario.15
Regarding determination of death, there is no federal legislation
which defines death in Canada. Some provinces, including Ontario,
have legislation that requires the determination of death be made by two
physicians. The United States’ Uniformed Determination of Death Act
specifies that death may be established by irreversible loss of neurological function (“brain death”), or irreversible cessation of cardiorespiratory function.16 The latter criteria is used in cases of DCDs.
Critics of DCD have noted that since the patients are sustained on
life support, their death is not inevitable. Further, DCD associates withdrawal of end-of-life care with organ procurement, in a manner nearly
ideal for transplantation. In order to prevent conflicts of interest, and to
maintain public support of DCD, it is imperative to ensure the medical
professions who decide to withdraw end of life care are not associated
with organ transplantation. This supports the “dead donor rule” that organ donation should neither cause nor hasten death.
Even with DCDs as a source for organ donation, the organ supply is
unable to meet demand. One strategy proposed to increase the supply is
switching to an “opt-out” system. Currently, Canada’s “opt-in” system
assumes one does not wish to donate unless they otherwise specify. In an
opt-out system, such as Spain’s, one is assumed to want to donate their
organs unless otherwise specified. In addition, given society’s reverence
for the importance of the human body, even though an individual’s rights
cease with death, an opt-out policy may be seen as a transgression of
the state. Further, public health campaigns to increase awareness and
improve cadaveric donation rates, including the recent Ontario Gift of
Life Campaign (http://www.giftoflife.on.ca/en/) have been widely implemented.
In most provinces, except Manitoba and Quebec, a patient’s recorded
consent constitutes legally-binding consent to organ donation. Nonetheless, patients are encouraged to make their substitute decision maker
aware of their choices, to ensure wishes are followed. In Ontario, the
TLGN Act notes consent is legally binding and provides legal immunity
to physicians who act in good faith with regards to organ procurement.
However, even if the deceased patient’s consent is clearly indicated,
physicians tend to consult family members before proceeding with organ procurement.
Living donor liver transplantion (LDLT) has been effectively used in
Canada for the past forty years. However, since a living donor has an estimated 0.2% mortality risk in adult-to-adult transplants, the procedure
is not without ethical considerations.17 Potential living donors are often
healthy individuals, for which the occurrence of even a low probability
of mortality is costly and should be avoided. This may explain the low
rate of LDLT in Canada. Even though they are willing and informed
donors, performing such a risky procedure violates the non-maleficence
principle. Further, these donors often incur significant costs from lost income and travel expenses. While it is ethically unacceptable to purchase
an organ, it may be fitting to compensate donors for their personal costs.
Currently Canada does not have a national strategy to reimburse living
organ donors.18
Donor compensation raises the issue of organ trafficking, in which
patients circumvent waitlists by paying for and receiving an organ and
26
medical care. When the procedure occurs in a foreign nation, it is common referred to as transplant tourism. Often the donor receives insufficient medical care, placing them at risk. The Canadian government
condemns organ trafficking, and the various provincial Human Tissue
Graft Acts directly outlaw paying for human tissues. The Criminal Code
outlaws any situation where a person is compelled to provide organs or
tissues. However, how this will be applied in relation to organ trafficking
remains to be seen. Further, Canadian physicians may feel uncomfortable treating patients who have been involved with organ trafficking.
Nonetheless, as with other cases in which physicians are conscientious
objectors, this cannot prevent a patient’s access to care.9
CONCLUSIONS
In many ways organ transplantation represents the pinnacle of our biomedical understanding of human physiology. Despite medical advances,
progress is hindered by the lack of supply, which has struggled to keep
up even with the introduction of living donation and DCDs as well as
massive public awareness campaigns. It is therefore the responsibility
of every health care provider to ensure patients are well-educated and
informed of the desperate need of organ donation. And as far as the question of why to donate, we asked Michael Bloch, the donor coordinator at
LHSC and his view is that:
“You have an opportunity of providing numerous people with improvement of their health and in fact save their life. It is human nature to
help fellow human beings, so if it is the last good thing you do in your
life, or even the only good thing you do in your life, I can’t see why you
will not”. 19
REFERENCES
1. Starzl T, Marchioro T, VonKaulla K, Hermann G, Brittain R, Waddell W. Homotransplantation of the Liver in Humans. Surg Gynecol Obstet. 1963; 117:
659–676.
2. Starzl T, Klintmalm GB, Porter KA, Iwatsuki S, Schroter GP. Liver Transplantation with use of Cyclosporin A and Prednisone. New England Journal
of Medicine. 1981; 305(5): 266-269.
3. Tat Fan S. Live Donor Liver Transplantation in Adults. Transplantation.
2006; 82(6): 723-732.
4. Multi-Organ Transplant Program: Statistics Page [Internet]. London (ON):
London Health Sciences Centre; cited 2012 April 4. Available from: http://
www.lhsc.on.ca/About_Us/MOTP/Statistics/index.htm
5. Gift of Life: Wait List by Organ Page [Internet]. Trilium Gift of Life Network;
cited 2012 May 10. Available from http://www.giftoflife.on.ca/en/statistics/
waitlistbyorgan.htm
6. Doward J, Campbell D. Transplant row over organs for drinkers [Internet].
The Guardian; cited 2009 Feb 15. Available from: http://www.guardian.
co.uk/society/2009/feb/15/liver-organ-transplants-alcohol
7. Miguet, M, Monnet E, Vanlemmens C, Gache P, Messner M, Hruskovsky S,
Miguet JP. Predictive factors of alcohol relapse after orthotopic liver transplantation for alcoholic liver disease. Gastroenterology Clinical Biology.
2004; 28(10): 845.
8. Ghobrial RM. Retransplantation for recurrent hepatitis C. Liver Transplantation. 2002; Oct;8(10 Suppl 1): S38-43.
9. Unger D. The Canadian Bioethics Companion: Chapter 7 - Organ Donation
[Internet]. 2011 [cited May 23]. Available from: http://canadianbioethicscompanion.ca/the-canadian-bioethics-companion/chapter-7-organ-donation/
10.Questions & Answers for Transplant Candidates Brochure [Internet]. Richmond (VA): United Network for Organ Sharing; 2011 May [cited 2012 May
10]. Available from http://www.unos.org/docs/MELD_PELD.pdf
11.11. Multiorgan Transplant Program: Organ Allocation Page [Internet].
London (ON): London Health Sciences Centre; cited 2011 Nov 2. Available
from: http://www.lhsc.on.ca/Patients_Families_Visitors/MOTP/Organ_and_
UWOMJ | 81:2 | Fall 2012
ETHICS AND LAW
Tissue_Donation /Allocation.htm.
12.Madwar S. National organ registry and allocation system remains remote.
CMAJ. 2011; 183(10): 109.
13.Pomfret EA, Fryer JP, Sima CS, Lake JR, Merion RM. Liver and intestine
transplantation in the United States, 1996-2005. American Journal of Transplant. 2007; 7(2): 1376.
14.Baker A. A closer look at organ donation after cardiocirculatory death in Canada. Canadian Journals Anaesthia. 2009; 56(11): 789-792.
15.LHSC leads the province in Donations after Cardiac Death (DCD) organ donors [Internet]. London (ON). London Health Sciences Centre; cited 2010
June 1. Available from: http://www.lhsc.on.ca/About_Us/LHSC/Media_
Room/Media_Releases/2010/June1.htm
16.Shemie S, Baker A, Knoll G, Wall W, Rocker G, Howes D, Chambers-Evans
J. Donation after cardiocirculatory death in Canada. CMAJ. 2006; 175(8):
S1–S24.
17.Middleton PF, Duffield M, Lynch SV, Padbury RT, House T, Stanton P, Maddern G. Living donor liver transplantation--adult donor outcomes: a systematic review. Liver Transplantation. 2006; 12(1): 24.
18.Klarenbach S, Garg AX, Vlaicu S. Living organ donors face financial barriers: A national reimbursement policy is needed. CMAJ. 2006; March, 174(6).
19.Bloch M. Donor Coordinator, LHSC Multi-organ Tranplant Team. Interviewed on 2012 May 10 (J. Fairbairn, & N. Argintaru, Interviewers).
UWOMJ | 81:2 | Fall 2012
27
Biologic agents in the management of
inflammatory bowel disease: is it worth it?
Tommy Choy (Meds 2015), Jessica Jackson (Meds 2015)
Faculty Reviwer: Dr. John Howard, MD, FRCPC (Department of Medicine and Paediatrics)
INTRODUCTION
Inflammatory Bowel Disease (IBD) represents a group of disorders that
affects the gastrointestinal (GI) tract. In this disease, an abnormal immune response in the body causes inflammation and ulceration of the
GI tract. The two main forms of IBD include Crohn’s disease (CD) and
ulcerative colitis (UC), which differ in their presentation and treatment.1
Crohn’s disease can affect any part of the GI tract, and the entire thickness of the intestinal wall is generally involved. Ulcerative colitis, on
the other hand, is limited to the rectum and colon and the exterior layers
of the intestinal wall are generally not affected. IBD is a lifelong disease that has a substantial impact on the quality of life of patients and
has a tremendous impact on a patient’s wellbeing. There are currently
no cures available for IBD and treatment is aimed towards keeping the
patient symptom-free.1
IBD is most commonly found in the developed world, although cases
have begun appearing more frequently in developing countries.2 Globally, Canada and Sweden have the highest incidence of both CD and
UC.2 It is estimated that more than 5000 cases of CD and 4000 cases of
UC are diagnosed in Canada each year, with a total of more than 200,000
Canadians living with one of these diseases at any given time.
The heavy burden that IBD imposes on patients in turn leads to
substantial financial costs for the Canadian healthcare system. Due to
the nature of IBD, these costs include both direct costs associated with
treating the disease and indirect costs such as lost productivity and time
missed from work. In a 2008 report by the Crohn’s and Colitis Foundation of Canada, it was found that the indirect cost associated with IBD is
approximately $1 billion dollars annually, with CD comprising roughly
$600 million of that value due to its higher prevalence.3 Direct medical
costs for IBD in Canada are estimated at over 750 million, with CD accounting for two-thirds of that value.3 Although these costs will continue
to increase as the prevalence of IBD grows, the distribution of the direct
medical costs have recently undergone significant changes due to the
introduction of new treatment options. The remainder of this article will
address these specific changes.
TREATMENT – PRE BIOLOGIC ERA
Prior to the introduction of biologics, the major categories of medication
prescribed for the treatment of IBD included aminosalicylates, corticosteroids and immunomodulators.4 In the event of failed medical therapy,
surgery was also considered. Resections were ideally conservative and
only undertaken for symptomatic patients.5
In both CD and UC, roughly one-third of total costs are concentrated
in the most severe patients (2% of all patients), who are often resistant
to traditional drug therapy.6 Medication costs are relatively inexpensive
when compared to the surgical interventions and related hospitalizations
28
required by these patients. In fact, surgical interventions account for
the greatest portion of the cost of IBD.6 Parenteral nutrition is another
costly intervention, which was reported to be responsible for majority of
overall pharmacy costs, despite infrequent use.6 Pharmaceuticals used
to represent less than 10% of overall health care cost related to the treatment of IBD, but this value has increased in the post-biologic era.3
TREATMENT - POST BIOLOGIC ERA
The first biologic agent was approved in 1998 and has since become a
popular IBD treatment choice. In most instances biologic agents are
initiated for patients who demonstrate an inadequate response to conventional therapies. There are currently four agents approved by the US
Food and Drug Administration for treating CD and one agent available
for use in UC. Infliximab is a murine chimeric monoclonal antibody
directed against tumor necrosis factor (TNF) -alpha, and can be used in
both acute attacks and maintenance therapies.7 It is also the only agent
available thus far in treating UC.8 Adalimumab and Certolizumab pegol
are humanized anti-TNF agents and are approved for use in treating patients who have lost response to Infliximab.7 Lastly, Natalizumab is a
humanized anti-alpha-4 integrin antibody and is used in patients who
cannot tolerate anti-TNF agents.7
In Canada, the cost for biologic agents was estimated to be over $110
million in 2008, comprising over two-thirds of overall drug cost.3 This
value has since increased with more agents appearing in the market.
World-wide, it is estimated that anti-TNF sales will peak at over 2 billion in the coming years, and the overall market for IBD will reach 4 billion US dollars in 2017.9 In addition to this growing selection of available agents, there has also been a change in the prescription habits of
physicians that has contributed to this increase in cost. The average time
from diagnosis to biologic treatment initiation has decreased from 7-8
years to 3-5 years, and it is likely that this trend of early treatment will
continue.5 In light of this trend, many studies have been done to study the
cost effectiveness of said agents.
COST EFFECTIVENESS OF BIOLOGIC AGENTS
Overall, most studies done to investigate the cost effectiveness of biologic treatment of IBD have demonstrated a decrease in necessary hospitalizations and surgical interventions. One study done at the University
of Chicago demonstrated a decrease in all surgeries by close to 40%,
emergency room visits by over 60% and decrease in hospitalization by
over 50%. 6 Another study in Spain reported that the cost of hospitalization was reduced from 60 percent down to 6% of total annual health expenditures for the treatment of IBD.10 Despite these positive outcomes,
these studies also indicated that the overall cost of IBD management
actually increased as a result of biologics usage. That being said, a more
costly intervention can still be cost effective as long as there is a sufficient increase in health outcome. For example, the National Institute
UWOMJ | 81:2 | Fall 2012
for Health and Clinical Excellence (NICE) suggests that an incremental
cost-utility ratio of 20,000 to 30,000 pounds (roughly $32000 to $48000
CAN dollars) per quality adjusted life year (QALY) gained can be considered cost effective.11
REFERENCES
Early studies reported induction therapies of infliximab for acute attacks to be greatly cost effective according to the above NICE guideline,
however, these were all short-term one year studies.12 This short time
frame likely led to an overestimate of the cost-effectiveness ratio due to
the chronic nature of IBD. Indeed, subsequent studies where the study
time horizon was expanded to 5 years revealed that the use of biologic
agents in acute attacks approached cost effectiveness. Lindsay et al. reported that Infliximab was cost effective for both luminal and fistulising
forms of CD, however, body weight was an important factor affecting
cost effectiveness.13 An evidence review group in the United Kingdom
reviewed the use of infliximab in exacerbations of UC and found an
incremental cost-utility ratio of roughly $32,000 US dollars, with the
results being sensitive to the patients’ colectomy rates.14 A systematic
review on the use of infliximab in CD was done by the National Institute
for Health Research and it reported that infliximab was cost-effective for
episodic treatment of active CD.11
2. Snapper SB, Podolsky DK. Epidemiology and genetic and environmental factors in inflammatory bowel disease in adults. In: Basow DS, ed. UpToDate.
Waltham, MA, 2010: UpToDate.
Contrary to the evidence found in induction therapies, studies have
reported poor results for the use of biologics in lifelong maintenance
therapies. French authors reported that the incremental cost per QALY
for infliximab in lifetime maintenance therapy of CD was more than 10
times that of the ratio for induction therapy.15 Similarly, Bodger et al.
found continuous therapy of infliximab to only be economically feasible
for up to 4 years.16 Evidence for models with a shorter time horizon
has also been mixed. “The Crohn’s Trial of the Fully Human Antibody
Adalimumab for Remission Maintenance trial” data reported that for a 5
year horizon, maintenance of adalimumab will result in an incremental
ratio of less than $48,000 per QALY in CD.17 “The Active Colitis Treatment trials” also reported similar findings for the use of infliximab in
UC patients.18 On the other hand, Kaplan et al. from the United States
have found an incremental ratio of $332,000 per QALY for infliximab
use in CD19, and a systematic review done by the Canadian Agency for
Drugs and Technologies in Health reported an incremental ratio of over
$200,000 for both infliximab and adalimumab in CD and $350,000 for
using infliximab in UC.20
8. Ulcerative Colitis – Treatment. [Internet]. University of Maryland Medical Center. 2008. Cited 2012 May 14. Available from: http://www.umm.
edu/patiented/articles/what_role_of_diet_ulcerative_colitis_000069_7.
htm#ixzz1txQ6iDaU
Part of the reason for the heterogeneity of results can be attributed
to differences in the cost of administering the agents between countries.
Although the cost for 100mg of infliximab is fairly stable at a price range
of ($700-900 US dollars), patients in the United States, but not the UK
must pay a substantial fee for the services of an infusion center.6 Greater
cost containments in both drug and administration costs will likely be
needed to ensure cost effective care. Another significant caveat of these
studies is the fact that indirect costs were not accounted for in their cost
effectiveness models. This is likely to cause a gross overestimation of
the cost effectiveness ratios for biologic agents.6 Lastly, it should be
noted that meta analyses were not performed as a result of significant
heterogeneity between studies, so a definitive answer on the matter is
unavailable.11,20
CONCLUSION
Biologic agents have been shown to provide clinical benefit in patients
with moderate to severe attacks of CD and UC. In turn, the increasing use of these agents in treatment of IBD has raised concerns about
whether or not these drugs are a cost-effective use of health care resources. Current evidence suggests that biologic agents are likely to be
cost effective when used to treat moderate to severe acute attacks of CD
and UC. Evidence for its use in maintenance therapy is inconclusive and
more research in this area is recommended.
1. The facts about inflammatory bowel disease. [Internet]. Crohn’s & Colitis
Foundation of America; 2011. Cited 2012 May 14. Available from: http://
www.ccfa.org/media/pdf/PPS_Brochures/ibdfactbook .
3. Crohn’s and Colitis Foundation of Canada. The burden of inflammatory bowel disease (IBD) in Canada. 2008. Toronto, Ontario
4. Mowat C, Cole A, Windsor A, Ahmad T, Arnott I, Driscoll R. Guidelines for
the management of inflammatory bowel disease in adults. Gut. 2011; 60(5),
571-607.
5. Bouguen G, Peyrin-Biroulet L. Surgery for adult crohn’s disease: What is the
actual risk? Gut. 2011; 1160(9), 1178-1181.
6. Cohen RD. The pharmacoeconomics of biologic therapy for IBD. Nature Reviews. Gastroenterology & Hepatology. 2010; 7(2), 103-109.
7. Mahadevan-Velayos, U. Biologic therapy for inflammatory bowel disease:
A clinical update. [Internet]. Medscape Gastroenterology. 2008. Cited 2012
May 14. Available from: http://www.medscape.org/viewarticle/582527
9. Examine the inflammatory bowel disease market-convenience and compliance drive market success. [Internet]. RedOrbit. 2008. Cited 2012 May
14. Available from: http://www.redorbit.com/news/health/1579576/examine_the_inflammatory_bowel_disease_marketconvenience_and_compliance_drive_market/
10.Park KT, Bass D. Inflammatory bowel disease-attributable costs and costeffective strategies in the United States: A review. Inflammatory Bowel Diseases 2011; 17(7), 1603-1609.
11.Dretzke J, Edlin R, Round J, Connock M, Hulme C, Czeczot J, Meads, C.
A systematic review and economic evaluation of the use of tumour necrosis
factor-alpha (TNF-α) inhibitors, adalimumab and infliximab, for Crohn’s disease. Health Technology Assessment. 2011; No. 15.
12.Di Sabatino A, Liberato L, Marchetti M, Biancheri P, Corazza GR. Optimal
use and cost-effectiveness of biologic therapies in inflammatory bowel disease. Internal and Emergency Medicine. 2011; 6 Suppl 1, 17-27.
13.Lindsay J, Punekar YS, Morris J, Chung-Faye G. Health-economic analysis:
Cost-effectiveness of scheduled maintenance treatment with infliximab for
crohn’s disease--modelling outcomes in active luminal and fistulizing disease
in adults. Pharmacology & Therapeutics. 2008: 28(1), 76-87.
14.Bryan S, Andronis L, Hyde C, Connock M, Fry-Smith A,Wang D. Infliximab
for the treatment of acute exacerbations of ulcerative colitis. Health Technology Assessment. 2011;14 Suppl 1, 9-15.
15.Jaisson-Hot I, Flourie, B., Descos, L., & Colin, C. (2004). Management for
severe crohn’s disease: A lifetime cost-utility analysis. International Journal
of Technology Assessment in Health Care, 20(3), 274-279.
16.Bodger, K. Cost-effectiveness of treatments for Inflammatory Bowel Disease.
Pharmacoeconomics. 2011; 29, 387-401.
17.Feagan, B. G., Panaccione R, Sandborn WJ, D’Haens GR, Schreiber S, Rutgeerts PJ, Mulani P. Effects of adalimumab therapy on incidence of hospitalization and surgery in crohn’s disease: Results from the CHARM study.
Gastroenterology. 2008; 135(5), 1493-1499.
18.Rutgeerts P, Sandborn WJ, Feagan BG, Reinisch W, Olson A, Johanns J, Colombel JF. Infliximab for induction and maintenance therapy for ulcerative
colitis. The New England Journal of Medicine. 2005; 353(23), 2462-2476.
19.Kaplan GG, Hur C, Korzenik J, Sands BE. Infliximab dose escalation vs.
initiation of adalimumab for loss of response in crohn’s disease: A cost-effectiveness analysis. Alimentary Pharmacology & Therapeutics. 2007; 26(11-
UWOMJ | 81:2 | Fall 2012
29
12), 1509-1520.
20.20. Assasi N, Blackhouse G, Xie F, Gaebel K, Marshall J, Irvine E, Goeree
R. Overview of anti-TNF-α drugs for refractory inflammatory bowel disease
(Technology overview No. 52). Ottawa: Canadian Agency for Drugs and
Technologies in Health. 2009.
30
UWOMJ | 81:2 | Fall 2012
HEALTH PROMOTION
Is it what you know or how you use it? A review
of nutrition knowledge and counseling among
medical professionals
Stephanie Gottheil (Meds 2014), Charlotte Hunter (Meds 2015)
Faculty Reviewer: Dr. John Howard, MD, FRCPC (Departments of Medicine and Paediatrics)
I
t is no secret that a number of chronic diseases, including cardiovascular disease, cancer, diabetes mellitus, and obesity, are causing
increasingly more disability and premature death around the world,
and that poor nutrition is a modifiable risk factor for these diseases.1
Given the prominent role of nutrition in the global burden of disease,
it is essential that today’s medical students receive an adequate amount
of nutrition education. It is also important that practicing physicians are
providing their patients with evidence-based nutritional counseling.
Based on a series of surveys conducted between 1999 and 2009,
62%-73% of medical schools in the United States were not meeting the
minimum target of 25 hours of nutrition education across the four years
of undergraduate medical education, as recommended by the National
Academy of Sciences.2 Canadian medical schools do not seem to be faring much better, at least according to students. A questionnaire given to 9
of the 17 Canadian medical schools revealed that 87.2% of medical students who responded felt that their program needed to devote more time
to nutrition instruction.3 There may be a number of barriers to achieving
the optimal amount of nutrition education, including limited time in the
curriculum, lack of nutrition specialists on faculty, and greater weight
being given to the treatment of disease rather than its prevention.2,3,4
The questionnaire given to Canadian medical students indicated
that some components of nutrition curricula may be stronger than others. The majority of respondents were comfortable with basic nutrition
concepts and the role of nutrition in health promotion.3 However, most
lacked confidence in their knowledge of nutritional requirements at different points in the lifecycle and their ability to discuss the role of nutrition in the treatment of disease.3 It is important that medical students are
exposed to nutrition education that provides them with practical skills,
such as nutritional assessment and counseling, in addition to the basic
science component.2
Regardless of the quality of nutrition education received, it is likely
that medical students will vary in their attitude towards nutritional counseling. Several studies have found that female medical students are more
likely to ask their patients about diet or engage in nutritional counseling than their male counterparts.5,6,7 It has also been found that medical students intending to specialize in primary care were significantly
more likely to consider nutritional counseling important than students
intending to pursue a career in a subspecialty.7 Interestingly, the same
study determined that medical students who consumed more fruits and
vegetables themselves were more likely to deem nutritional counseling
relevant to their clinical practice.7 Educational methods for increasing
students’ provision of nutritional advice might therefore include demonstrating the relevance of nutrition in subspecialty practice and encouraging students to improve their own diet and knowledge of healthy cooking.
Some programs have found ways to overcome the many barriers that
stand in the way of achieving adequate nutrition education in medical
schools. The University of Arizona College of Medicine managed to
increase the time devoted to nutrition instruction in their program from
35 hours to 75 hours by implementing an integrated nutrition curriculum
that incorporated nutritional topics into a variety of courses, including
biochemistry, social and behavioural sciences, and preparation for clinical medicine.4 This approach also improved the students’ clinical application of nutritional knowledge and skills. Nutrition scores on the
Objective Structured Clinical Examination (OSCE) were significantly
higher (P < 0.05) for students who had been exposed to the new curriculum, compared to those who had graduated before it was implemented.4
While an integrated curriculum represents one approach to contend
with a limited number of lecture hours, another way to overcome this
barrier might be to have students complete some of their nutrition education online. Researchers at the University of North Carolina at Chapel
Hill have developed an online nutrition curriculum called the Nutrition
in Medicine (NIM) project, which was being used by 90 of the 156
American medical schools when their paper was published in 2010.2
The online modules are designed so that users will develop practical
skills such as assessing a patient’s nutritional status or prescribing nutritional interventions as treatment.2 This kind of online program would
likely help to address existing deficits in nutritional education, like the
clinical application of nutritional knowledge, while compensating for
time constraints and standardizing nutrition instruction across different
medical schools.
When one considers the current state of knowledge among primary
care physicians, an interesting pattern emerges. Over 80% of Canadian
family physicians rated their medical school nutrition training as inadequate. Many doctors stated that they wanted more direct training
on nutrition during their undergraduate and postgraduate education.8,9
However, surveys asking physicians about their current state of knowledge demonstrate that over 60% believe they know ‘very much’ about
prescribing diets for weight-loss10 and over 75% believe their nutritional
knowledge is “up-to-date”.11 In one focus group, most doctors agreed
that their level of nutritional knowledge was adequate to deal with most
common health problems.12 Indeed, when given objective tests of nutrition knowledge, most family physicians answer the majority of questions correctly, albeit with certain gaps.11 When asked about the sources
of their nutritional information, most physicians cite self-directed learning and reading,8,12 while some cite Continuing Medical Education
(CME) courses.13
Most studies agree that primary care physicians seem to have an adequate level of knowledge about nutrition. Nonetheless, only 40% of
obese patients are counseled to lose weight by their physician10 and there
is a significant difference between the number of patients that would ben-
UWOMJ | 81:2 | Fall 2012
31
HEALTH PROMOTION
efit from dietary advice and the number of patients that actually receive
counseling.8 When asked about barriers to providing dietary advice, the
answers were mixed. A Canadian study cited lack of time and lack of
compensation as the largest barriers,8 and lack of time was echoed in a
UK study as well.14 A Scandinavian study reported lack of nutritional
knowledge as the primary barrier9 and an Israeli study mentioned patient
apathy and non-compliance as a barrier to providing nutritional advice.15
Patient and physician beliefs can also be barriers to effective nutritional counseling. While the large majority of primary care physicians
believe that counseling is part of their role,15,16 many doctors believe
that nutritional counseling usually does not help their patients13,14 and report feeling frustrated and pessimistic about the effectiveness of dietary
advice.10 Interestingly, physicians that reported more nutritional knowledge were more likely to discuss nutrition with their patients, and more
likely to believe that it was effective.8,10 Patients report lack of nutritional
knowledge as the primary barrier to making dietary change; physicians,
however, overwhelmingly believe patient apathy is the biggest barrier.14
Both patients and physicians often believe nutritional counseling is not
necessary without an active medical diagnosis, with patients much less
likely to view obesity as a medical diagnosis.15,16
Moore et al.14 provide a compelling explanation for the gap between
having adequate nutritional knowledge and providing effective nutritional counseling. They believe that the problem lies in knowledge
translation – the ability to apply knowledge in a way that leads to behavioural change. Physicians are primarily trained in the management
of disease, and not in health promotion or preventative medicine. Physicians that consciously include motivational statements in their dietary
advice, or who were trained on motivational counseling techniques,
were more successful in achieving dietary change from their patients.8,14
Pignone et al.17 defines counseling as “a cooperative mode of interaction to assist patients in adopting behaviours associated with improved
health outcomes”. There are many styles of counseling used by physicians. An informational style includes providing patients with nutritional facts and written materials. A reference style includes referring
patients to a dietician for specific nutritional advice. A motivational style
includes a holistic assessment of the patient’s readiness for change, and
is widely considered the most effective method.12,14 Many physicians are
already attempting to provide strong nutritional counseling to their patients, and 80% believe that they are “occasionally” successful in helping patients make dietary change.14
A recent systematic review describes nutritional counseling techniques and interventions that are most successful at improving patient
health.17 This review included 21 RCTs with objective endpoints – biochemical markers (i.e. serum triglycerides) or anthropomorphic measurements (i.e. waist circumference). The most effective interventions
had a number of shared characteristics. They included an initial dietary
assessment, family involvement with social supports, group counseling,
and goal-setting. They also discussed not only food intake, but also food
preparation techniques. While these are admirable goals, it is not always
feasible in a primary care setting. Eaton et al.18 found that physicians
spend an average of 1 minute discussing nutrition in a routine primary
care appointment. However, Pignone et al.17 also discussed ‘mediumintensity’ interventions that were moderately effective and would be feasible in primary care. These included a combination of targeted self-help
materials, given directly by the health care provider, followed by brief,
face-to-face provider advice. Moore et al.14 supports this finding, stating that the goal of primary care physicians should be to reinforce and
legitimize the available public health advice on nutrition.
How can we design educational programs that will help medical students and current physicians develop into strong nutritional counselors?
32
The introduction of innovative nutrition modules should focus on two
main areas: the application of nutritional knowledge in the prevention of
disease and management of common chronic conditions, as well as techniques for counseling and motivating patients to change their dietary
habits. New interventions, designed for both medical school and primary care practice, seem promising in their ability to meet these goals.
Nutrition is a vital tool in primary prevention and health promotion, and
hopefully will be increasingly recognized as such in the medical community.
REFERENCES
1. World Health Organization. Diet, nutrition and the prevention of chronic disease: Report of a Joint WHO/FAO Expert Committee. 2003. WHO technical
report series 916. World Health Organization, Geneva, Switzerland. 1-149.
2. Adams KM, Kohlmeier M, Powell M, Zeisel SH. Nutrition in medicine: nutrition education for medical students and residents. Nutr Clin Pract. 2010
Oct;25(5):471-480.
3. Gramlich LM, Olstad DL, Nasser R, Goonewardene L, Raman M, Innis S, et
al. Medical students’ perceptions of nutrition education in Canadian universities. Appl Physiol Nutr Metab. 2010;35:336-343.
4. Taren DL, Thomson CA, Koff NA, Gordon PR, Marian MJ, Bassford TL, et
al. Effect of an integrated nutrition curriculum on medical education, student
clinical performance, and student perception of medical-nutrition training.
Am J Clin Nutr. 2001;73:1107-1112.
5. Dayal AK, Van Eerden P, Gillespie L, Katz NT, Rucker L, Rosett JW.
Case-based nutrition teaching for medical students. J Nutr Educ Behav.
2008;40:191-192.
6. Schulman JA, Karney BR. Gender and attitudes toward nutrition in prospective physicians. Am J Health Behav. 2003 Nov-Dec;27(6):623-632.
7. Spencer EH, Frank E, Elon LK, Hertzberg VS, Serdula MK, Galuska DA.
Predictors of nutrition counseling behaviors and attitudes in US medical students. Am J Clin Nutr. 2006;84:655-662.
8. Wynn K, Trudeau JD, Taunton K, Gowans M, Scott I. Nutrition in primary
care: Current practices, attitudes, and barriers. Can Fam Physician. 2010
Mar;56(3):e109-16.
9. Mowe M, Bosaeus I, Rasmussen HH, Kondrup J, Unosson M, Rothenberg
E, Irtun O, Scandinavian Nutrition Group. Insufficient nutritional knowledge
among health care workers? Clin Nutr. 2008 Apr;27(2):196-202.
10.Ferrante JM, Piasecki AK, Ohman-Strickland PA, Crabtree BF. Family physicians’ practices and attitudes regarding care of extremely obese patients.
Obesity (Silver Spring). 2009 Sep;17(9):1710-6.
11.Moore H, Adamson AJ. Nutrition interventions by primary care staff: A
survey of involvement, knowledge and attitude. Public Health Nutr. 2002
Aug;5(4):531-6.
12.van Dillen SM, Hiddink GJ, Koelen MA, de Graaf C, van Woerkum CM.
Identification of nutrition communication styles and strategies: A qualitative
study among dutch GPs. Patient Educ Couns. 2006 Oct;63(1-2):74-83.
13.Kahn RF. Continuing medical education in nutrition. Am J Clin Nutr. 2006
Apr; 83(4):981S-4S.
14.Moore H, Adamson AJ, Gill T, Waine C. Nutrition and the health care agenda:
A primary care perspective. Fam Pract. 2000 Apr;17(2):197-202.
15.15. Endevelt R, Werner P, Karpati T, Ami LB. Which physicians are best prepared to advise seniors about nutrition? A pilot survey in israel. J Nutr Elder.
2009 Jan-Mar;28(1):96-104.
16.16. McClinchy J, Dickinson A, Barron D, Thomas H. Practitioner and lay perspectives of the service provision of nutrition information leaflets in primary
care. J Hum Nutr Diet. 2011 Dec;24(6):552-9.
17.Pignone MP, Ammerman A, Fernandez L, Orleans CT, Pender N, Woolf S,
Lohr KN, Sutton S. Counseling to promote a healthy diet in adults: A summary of the evidence for the U.S. preventive services task force. Am J Prev
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HEALTH PROMOTION
Med. 2003 Jan;24(1):75-92.
18.Eaton CB, Goodwin MA, Stange KC. Direct observation of nutrition counseling in community family practice. Am J Prev Med. 2002 Oct;23(3):174-9.
UWOMJ | 81:2 | Fall 2012
33
INTERDISCIPLINARY
Acupuncture in the treatment of irritable bowel
syndrome
Alexander Yan (Meds 2015), Yin Hui (Meds 2015) and Caitlin VanDeCappelle (Meds 2014)
Faculty Reviewer: Dr. Larry Schmidt, MD, CCFP (Department of Family Medicine)
INTRODUCTION
Irritable bowel syndrome (IBS) is a gastrointestinal disorder characterized by chronic abdominal pain and irregular bowel function in the
absence of an organic cause. It is estimated to affect ten to fifteen percent of the North American population, with higher prevalence among
younger and female patients.1 While only a minority of patients seek
medical treatment, IBS constitutes more than a quarter of gastroenterology referral each year.1
As IBS is a chronic condition with no known cure, treatment plans
have focused on relief of abdominal symptoms and addressing any other
patient concerns.1 This has grown to include alternative therapies, including acupuncture. In 2003, the World Health Organization listed irritable colon syndrome as a syndrome for which “acupuncture is worth
trying because treatment by conventional and other therapies is difficult”, though they stress that there are only individual controlled trials
reporting some therapeutic effects.2 At present time, the evidence for
effectiveness of acupuncture for treatment of IBS remains inconclusive.
Acupuncture theory, recent research findings and implications of acupuncture use in IBS treatment will be discussed below.
Acupuncture is an ancient form of Chinese medicine which involves inserting solid, ‘atraumatic’ and stainless steel needles into the
skin at specific points on the body. These points, known as acupoints,
have been theorized to have a lower resistance to passage of electricity than the surrounding skin, and are connected by the flow of Qi, or
energy, throughout the body.3 Any imbalance, obstruction or misdirection of this movement of Qi is thought to lead to disease, or potentially
increase susceptibility to illness.3 Supporters of the practice believe that
acupuncture is used to correct the Qi imbalance, restoring a balance in
autonomic nervous system function, treating symptoms and preventing
illness.3 Specifically for IBS, acupuncture is thought to restore balance
to the autonomic nervous system, which is in dysrhythmia due to disparity in Qi of the spleen, kidney and/or liver.3 Research has suggested
that treatments of traditional and electroacupuncture can influence the
physiology of the gastrointestinal tract, including altering the motility,
pain threshold, hormone levels and acid secretion of the gastrointestinal
system.4-7 Although there has been no conclusive evidence regarding its
effects in IBS, many acupuncturists now cite IBS as a potential indication for their treatments.
diarrhea, constipation, or abdominal pain. However, in a study using
Chinese herbal medicine as the control, the effect of acupuncture was
found to be statistically significant.8 In a German study by Schneider
et al (2007), effect of acupuncture was assessed based on autonomic
nervous system response, pain, and quality of life.9 Sham acupuncture
served as the control. Autonomic nervous system response to acupuncture was measured by salivary cortisol levels and changes in heart rate
during a tilt table test. It was found that for both groups of patients,
there was an improvement in health related quality of life as indicated
by patient responses to questionnaires. However, for the group treated
with acupuncture, pain control was statistically improved after 10 treatments. It was also found that patients treated with acupuncture had lower
salivary cortisol levels, and reduced heart rate increases during the tilt
table test, indicating increased parasympathetic tone.
On the other hand, several studies with double blind, sham controlled
trials have yet to convincingly prove the benefit of acupuncture for treating IBS.10, 11 In a recent study by Lembo et al (2009), while it was found
that interactions with the health care professional performing either the
sham or real acupuncture offered improvement in IBS symptoms when
compared to no intervention, there were no differences in improvement
between the two acupuncture interventions.11
The majority of studies investigating the benefits of acupuncture in
IBS were under powered, with the largest randomized control trial including only 230 patients.11 Study methodologies and acupuncture techniques were heterogeneous, specifically in the number and duration of
treatments.8, 12 These variations made it difficult for reviewers to pool
together smaller studies to elucidate the treatment effect.8
DISCUSSION
LITERATURE REVIEW
Acupuncture is becoming increasingly recognized in Canada as an adjunct therapy and health care practitioners are beginning to incorporate
acupuncture into their skills of practice. In most Canadian provinces,
health care practitioners require extra training beyond their basic professional training to perform acupuncture. The standard for training is
set by the regulatory bodies for each profession, but in many provinces
there are still no standards.3 Currently in Ontario, the practice of acupuncture is regulated by the Traditional Chinese Medicine Act, 2006.13
The Ontario government is also in the process of establishing a college
whose mandate will be to oversee the implementation of policies and
regulations relating to the acupuncturist profession.
Current evidence show conflicting results over the benefit of acupuncture. Lim et al (2006) reviewed six randomized control trials of poor
quality and heterogeneous intervention, and found the benefit of acupuncture use in IBS to be inconclusive.8 They noted that in studies comparing acupuncture with sham acupuncture, treatments did not offer
improvements in overall well-being, or in individual symptoms such as
Any discussion about the use of acupuncture in clinical practice
should always take into account the patient perspective. Current drug
therapy for IBS provides little benefit to patients, thus it is not surprising
that almost 50% of IBS patients turn to complementary and alternative
medicine therapies.14 Furthermore, despite the lack of evidence to provide a convincing argument for an actual therapeutic benefit of acupunc-
34
UWOMJ | 81:2 | Fall 2012
INTERDISCIPLINARY
ture compared to sham acupuncture, there is at least some perceived
benefit due to a placebo effect. In fact, all trials indicated a significant
increase in quality of life independent of the kind of acupuncture (real or
sham).15 It is important to note that the study quality was poor in many
of these trials. Further investigation is necessary to delineate the efficacy
of acupuncture in the treatment of IBS. Finally, there is no evidence to
indicate any potential harm for the use of acupuncture in the treatment of
IBS. Given these circumstances, physicians should consult their patients
about the options they are considering and not be openly dismissive of
acupuncture as an adjunct therapy.
On a final note, while many studies focus on the effect of traditional
acupuncture compared to placebo (i.e., sham acupuncture), considerably
fewer studies compare acupuncture with standard drug therapy. Certainly, while the use of tricyclic antidepressants in the treatment of IBS is
supported by strong clinical evidence,14, 16 there is little evidence to support the use of antispasmodics or selective serotonin reuptake inhibitor
antidepressants.14, 17, 18 We believe that current drug therapies deserve the
same level of scrutiny as acupuncture. Lundeberg et al (2011) suggest
that the therapeutic effects of acupuncture can be compared to those of
standard treatment, taking into consideration individual responses and
circumstances, before deciding on the use or disuse of acupuncture in
the treatment of IBS.19
IBS remains a difficult syndrome to treat, with the main focus of
management on relief of symptoms. Although the research remains inconclusive, acupuncture may play a role in alleviating some gastrointestinal symptoms and increasing the quality of life for some IBS patients.
It is up to us as future physicians to work with our patients to determine
the best management plan combining allopathic and naturopathic medicine.
10.Schneider A, Enck P, Streitberger K, Weiland C, Bagheri S, Witte S, Friederich H, Herzog W, Zipfel S. Acupuncture treatment in irritable bowel syndrome. Gut 2006 May 01;55(5):649-54.
11.Lembo A, Conboy L, Kelley J, Schnyer R, McManus C, Quilty M, Kerr C,
Drossman D, Jacobson E, Davis R, et al. A treatment trial of acupuncture in
IBS patients. Am J Gastroenterol 2009;104:1489–1497.
12.Maneerattanaporn M, Chey W. Acupuncture for irritable bowel syndrome:
Sham or the real deal? Gastro 2010;139(1):348-350.
13.Traditional Chinese Medicine Act, 2006, CHAPTER 27, CHAPTER 27 .
14.Shen YH, Nahas R. Complementary and alternative medicine for treatment of
irritable bowel syndrome. Can Fam Physician 2009 Feb;55(2):143-8.
15.Schneider A, Streitberger K, Joos S. Acupuncture treatment in gastrointestinal
diseases: A systematic review. World J Gastroenterol 2007 Jul 7;13(25):341724.
16.Jackson JL, O’Malley PG, Tomkins G, Balden E, Santoro J, Kroenke K.
Treatment of functional gastrointestinal disorders with antidepressant medications: A meta-analysis. Am J Med 2000 Jan;108(1):65-72.
17.Schoenfeld P. Efficacy of current drug therapies in irritable bowel syndrome: What works and does not work. Gastroenterol Clin North Am 2005
Jun;34(2):319,35, viii.
18.McFarland LV. State-of-the-art of irritable bowel syndrome and inflammatory bowel disease research in 2008. World J Gastroenterol 2008 May
7;14(17):2625-9.
19.Lundeberg T, Lund I, SingA, Näslund J. Is placebo acupuncture what it is intended
to be? Evidence-Based Complementary and Alternative Medicine 2011;2011.
REFERENCES
1. Clinical manifestations and diagnosis of irritable bowel syndrome. In: UpToDate, Talley, N.J. (Ed), UpToDate, Waltham, MA, 2012. [Internet]; c2012
[cited 2012 04/20].
2. Xie Z. Acupuncture: Review and analysis of reports on controlled clinical
trials. 2003;World Health Organization.
3. Regulation in Canada [Internet]; c2008 [cited 2012 04/20]. Available from:
http://www.afcinstitute.com/AboutAcupuncture/WhatisAcupuncture/tabid/73/Default.aspx.
4. Xing, J., Larive B., Mekhail, N., Soffer, E. Transcutaneous electrical acustimulation can reduce visceral perception in patients with the irritable bowel
syndrome: A pilot study. Altern Ther Health Med 2004;10(1):38.
5. Tian, S.L., Wang, X.Y., and Ding, G.H. Repeated electro-acupuncture attentuates chronic visceral hypersensitivity and spinal cord NMDA receptor phosphorylation in a rat irritable bowel syndrome model. Life Sci
2004;10(1):38,39-42.
6. Lux, G., Hagel, J., Backer, P., Backer, G et al. Acupuncture inhibits vagal gastric acid secretion stimulated by sham feeding in healthy subjects. GUT: An International Journal of Gastroenterology and Hepatology.
2004;8(8):1026,1027-1029.
7. Lin, X., Liang, J., Ren J., et al. Electrical stimulation of acupuncture points
enhances gastric myoelectrical activity in humans. The American College of
Gastroenterology 1997;92(9).
8. Lim B, Manheimer E, Lao L, Ziea E, Wisniewski J, Liu J, Berman B. Acupuncture for treatment of irritable bowel syndrome. Cochrane Database of
Systematic Reviews 2006(4).
9. Schneider A, Weiland C, Enck P, Joos S, Streitberger K, Maser-Gluth C, Zipfel S, Bagheri S, Herzog W, Friederich HC. Neuroendocrinological effects of
acupuncture treatment in patients with irritable bowel syndrome. Complement Ther Med 2007 12;15(4):255-63.
UWOMJ | 81:2 | Fall 2012
35
HEALTH AND TECHNOLOGY
The use of gene expression profiling in the
personalization of colorectal cancer treatment
Laura Callan, MASc (Meds 2015) and Melissa J. MacPherson, PhD (Meds 2014)
Faculty Reviewer: Dr. Brian Dingle, MSc, MD, FRCPC, Division of Medical Oncology
C
olorectal cancer (CRC) is the third most common cancer
in Canada.1 This year in Ontario, it is estimated that 8700
people will be diagnosed with CRC and 3450 people will die
of the disease.2 Due to the high mortality rate of CRC, screening programmes have been designed to screen the population for CRC prior to
the onset of symptoms. The high burden of disease CRC causes has also
made the field of CRC screening, diagnosis and treatment a prime area
for the development of novel medical technology. Historically, these
technologies have been limited to the fields of biochemical testing of
stool and fiber optic visualization of the colon using the colonoscope.
A new and exciting field for technology development is the application
of molecular genetics in the profiling of colorectal tumours. Genetic
profiling will allow clinicians to develop a personalized treatment plan
for the administration of chemotherapeutic agents and biologics in the
treatment of CRC. Personalized medicine has the potential to improve
outcomes by selecting the chemotherapeutic agent that has the best likelihood of effectiveness for a given patient’s specific tumour. In order for
this practice to become the standard of care, links between genetic profiles and chemotherapeutic effectiveness must be known and technologies for analysing the relevant gene profiles must be developed. The
application of this technology to stage II CRC in particular is an active
field of research.
Currently, the five year survival rate for stage I CRC is approximately 93%. This survival rate falls to approximately 80% for patients with
stage II disease.3 The effectiveness of adjuvant chemotherapy for stage
II CRC disease is currently an area of debate in the field of oncology.4
Moertel et al. conducted a retrospective study looking at patients with
stage II CRC to identify clinical characteristics that are predictive of recurrence of disease in order to identify patients who might benefit from
adjuvant chemotherapeutic treatment. These characteristics include
T4 lesions, bowel obstruction and tumour perforation.5 Patients with
high risk stage II disease, identified using these characteristics, are often
treated with adjuvant chemotherapy, despite the lack of validation with a
randomized clinical trial.4 An analysis of the American SEER-Medicare
database--one of the largest medical databases in the United States--has
demonstrated that patients with stage II CRC who received adjuvant
fluorouracil based chemotherapy did not have improved outcomes with
either high risk or low risk disease.6 Conversely, the QUASAR study
has shown that the standard chemotherapy regimen of fluorouracil plus
leucovorin produces a 3% survival benefit in stage II CRC; however, the
toxicity of the treatment causes death in 0.5% of patients.7 To make matters more complicated, the addition of oxaliplatin to a chemotherapeutic
regimen of fluorouracil and leucovorin improves the outcome in stage
III CRC but does not improve the 6 year survival outcomes of stage II
CRC.4,7 This surprising finding highlights the need for improving the
clinical criteria for selecting stage II CRC patients who will benefit from
adjuvant chemotherapeutic treatment. The findings in this paper also
36
suggest that CRC is not necessarily a stepwise progression from stage II
to stage III disease and demonstrates the need for further research into
the molecular biology of stage II disease.
Despite the criteria for high risk stage II CRC outlined above and the
limitations of these criteria, the morbidity associated with treatment for
stage II CRC could be greatly reduced if physicians were able to further
delineate which patients could benefit from adjuvant treatment. The
molecular genetic profiling of a patient’s colorectal tumour could potentially yield this information by analysing for the expression of genes
which are known to respond better to adjuvant chemotherapy. While
this approach is very exciting and holds great promise, physicians and
researchers need to make sense of the extensive data that can be generated using a genomics approach. Knowing the expression levels of
all the genes in the CRC tumour is not a practical approach to deciding treatment options for the disease. Several research groups have addressed this challenge by selecting groups of genes to profile in an effort
to determine which genes in stage II CRC’s are clinically significant for
recurrence.
An interesting product that is beginning to become available in the
clinic is the Oncotype Dx Colon Cancer 12 gene assay. This assay measures the expression levels of seven cancer related genes (Stromal Group:
BGN, FAP, INHBA; Cell Cycle Group: MYC, MK167, MYBL2; Early
Response Group: GADD458) and normalizes these genes to a group of
reference genes that have very little variability in expression (ATP5E,
GPX1, PGK1, VDAC2, UBB).8 The seven cancer related genes were
selected based on the results of a series of development studies which
included four independent cohorts for a total of over 1800 patients.
Starting with a panel of 761 genes known to be associated with CRC,
the seven genes most associated with recurrence risk and differential
benefit with adjuvant chemotherapy in stage II CRC were selected to be
used on the Oncotype Dx 12 gene assay.7 Tissue samples for use in this
particular assay are fixed in formalin, a significant technical advancement over other assays since it means that pathology samples and gene
expression profiling can be obtained from one tumour sample. It also
allows gene expression profiling to be conducted on previous biopsies
or tumour resections. Briefly, RNA is extracted from the formalin fixed
tumour and quantified to determine the amount of RNA present in the
sample. The RNA is then reverse transcribed to complementary DNA
using a gene specific primer for each assay gene. The expression levels
of the 12 genes are then measured using quantitative polymerase chain
reactions (PCR) (see Figure 1 for a schematic of the assay). After the
molecular biologic analysis is completed, a recurrence score between
0 and 100 is then assigned based on an algorithm outlined by ClarkLangone et al..8 A low score (≤30) corresponds to a 3 year recurrence
risk of 8%, an intermediate score (31-40) has a 3 year recurrence risk
of 11% and a high score (≥41) has a 3 year recurrence risk of 25%.7
UWOMJ | 81:2 | Fall 2012
This algorithm takes the combined expression values from each of the
gene groups (Stromal, Cell Cycle and Early Response), allowing for coexpression, and combines these values with varying weights to create
an overall recurrence score, an individualized risk estimate for colon
cancer recurrence. While initial results based on a retrospective analysis
using the QUASAR trial do show an association between the recurrence
risk score and prognosis, the predictive value of the recurrence score for
treatment benefit has not yet been shown. Further trials are underway
to determine the full clinical effectiveness of the Oncotype Dx Colon
Cancer Assay.9
Other similar products on the market include the Coloprint 18 gene
assay;10 however, this assay is of limited utility since it only makes use
of fresh frozen tumour samples. The Oncotype Dx Colon Cancer Assay
uses formalin fixed tissues allowing for the flexibility to also perform
pathological analysis of the same tumour sample. While these emerging
technologies are not likely to replace the role of pathological evaluation
of tumours in the diagnosis and staging of colorectal cancers within our
lifetime, they may have the ability to complement current practices by
providing more detailed information on which treatment options are best
for a particular patient. Despite their promise, several questions need to
be addressed regarding their utility. Since a patient has many CRC tumours and not all tumours have an identical genotype, will the assays be
valid at selecting those patients who will benefit from adjuvant chemotherapy? Moreover, since the genotype of a CRC tumour changes during the course of treatment due to the development of drug resistance,
will the assay be a worthwhile clinical tool in the treatment of the ever
evolving stage II CRC tumour? Also, how much of a survival advantage
will adjuvant therapy provide and will the assay be cost-effective when
analyzed using QALY? Despite these questions, the use of molecular
cDNA
reverse transcription
to cDNA
RNA quantified using
fluorescent dye
quantitative PCR
and detection with
fluorescent probes
RNA extracted
5'
3'
fixed colorectal tumour
5'
pathology
3'
5'
Analysis with
Oncotype Dx
Algorithm and
Scoring
3'
Figure 1: A schematic diagram illustrating the Oncotype Dx Colon Cancer Assay. A colorectal tumour is fixed in formalin, sent for pathological3'analysis and used concurrently in the Oncotype Dx assay. RNA is extracted from the tumour and is quantified using fluorescent dyes. A known amount of
RNA is added to a reverse transcription reaction. The RNA is reverse transcribed to complementary DNA (cDNA) using primers specific for each of
the 12 genes of interest. Quantitative polymerase chain reaction (qPCR) is performed using the cDNA and fluorescent probes. The probes are specific
for each gene of interest and have a fluorescent molecule (star) bonded to one end and a quencher (spiral) that stops the fluorescence bonded to the
opposite end. During the PCR reaction the Taq polymerase enzyme cleaves the probe thus, releasing the fluorescent molecule from the quencher. The
amount of fluorescent signal in the reaction increases and is measured. The expression levels of the genes of interest are normalized against the reference genes using the Oncotype Dx algorithm.
UWOMJ | 81:2 | Fall 2012
37
genetics tools in personalized cancer treatment is sure to become a reality over the course of our medical careers.
REFERENCES
1. Minister of Health;. Screening for Colorectal Cancer. Health Canada. [Online] July 2007. [Cited: September 20, 2012.] http://www.hc-sc.gc.ca/hl-vs/
iyh-vsv/diseases-maladies/colorectal-eng.php.
2. Colorectal Cancer Association of Canada. Colorectal Cancer Statistics.
Colorectal Cancer Association of Canada. [Online] 2012. [Cited: September
20, 2012.] http://www.colorectal-cancer.ca/en/just-the-facts/colorectal/.
3. Colon Cancer Survival Rates With the New American Joint Committee on
Cancer Sixth Edition Staging. O’Connell, Jessica B, Maggard, Melinda A and
Ko, Clifford Y. 95(19), Journal of the National Cancer Institue, 2004.
4. Oxaliplatin As Part of Adjuvant Therapy for Colon. Mayer, Robert J. 30(27),
Journal of Clinical Oncology, 2012.
5. Intergroup study of fluorocil plus levamisole as adjuvant therapy for stage II/
Dukes’ B2 Colon Cancer. Moertel, C G, Fleming, T R and Macdonald, J S. 13
p.2936-2943, Journal of Clinical Oncology, 1995.
6. Adjuvant chemotherapy for stage II colon cancer with poor prognostic features. O’Connor, E S, Greenblatt, D Y and LoConte, N K. 29 p.3381-3388,
Journal of Clinical Oncology, 2011.
7. Relationship Between Tumor Gene Expression and Recurrence in Four Independent Studies of Patients With Stage II/III Colon Cancer Treated With
Surgery Alone or Surgery Plus Adjuvant Fluorouracil Plus Leucovorin .
O’Connell, Michael J, et al. 28(25), Journal of Clinical Oncology, 2010.
8. Translating Tumor Biology into Personalized Treatment Planning: analytical
performance characteristics of the Oncotype DX Colon Cancer Assay. ClarkLangone, Kim M, et al. 10(691), BioMed Central Cancer, 2010.
9. Prognostic and Predictive Markers in Stage II Colon Cancer: Is There a Role
for Gene Expression Profiling? Kelley, Robin K and Venook, Alan P. 10(2),
Clinical Colorectal Cancer, 2011.
10.Genetics: An 18-gene signature (ColoPrint®) for colon cancer prognosis.
Tan, Iain B and Tan, Patrick. 8 p.131-133, Nature Reviews Clinical Oncology, 2011.
11.Recent advances in systemic therapy. New diagnostics and biological predictors of outcome in early breast cancer. Oakman, Catherine, et al. 11(2), Breast
Cancer Research, 2011.
12.Adjuvant Therapy With Fluorouracil and Oxaliplatin in Stage II and Elderly
Patients (between ages 70 and 75 years) With Colon Cancer. Tournigand,
Cristophe, et al. 30(27), Journal of Clinical Oncology, 2012.
38
UWOMJ | 81:2 | Fall 2012
PROFILES
Gastroenterology profiles: Dr. John Howard
Lauren Sham (Meds 2014), Abdul Naeem (Meds 2014), Joyce Zhang (Meds 2015)
Faculty Reviewer: Dr. John Howard, MD, FRCPC (Departments of Medicine and Pediatrics)
D
uring the “Transcending Borders” conference hosted by the
University of Western Ontario earlier this year, Dr. John Howard offered some sage advice to eager students: to focus on the
things we can change, and celebrate our small successes. This genuine
counsel is perhaps the result of a multitude of experiences aimed at producing positive change. Currently the Chief of Paediatric Gastroenterology and Assistant Program Director for Paediatrics at Victoria Hospital
in London, Ontario, Dr. Howard has also held the position of Assistant
Dean of Undergraduate Medicine, where he spearheaded the development of a new undergraduate curriculum. He is also the Chair of the
Canadian Association of Physicians for the Environment (CAPE). His
passion for medical teaching is immediately felt the second he enters a
lecture hall, and he has been recognized many times as the recipient of
numerous teaching awards.
As a kid, Dr. Howard had his heart set on becoming a veterinarian,
but as he says, he just happened to “stumble into medicine.” Looking
back, he sees that this is probably why he is in paediatrics: “Saying ‘My
cow’s not performing well’ is kind of like saying ‘My kid’s not performing well’ – they’re both very observational!” He completed his medical
training at Queen’s University and his residency in Internal Medicine at
the University of Western Ontario with subspecialty training in Gastroenterology. When practicing adult gastroenterology at Victoria Hospital
in London, he shared the paediatric patients because they didn’t have
anyone to look after them specifically. In 2004, he made the switch from
adults to mainly kids. He has the privilege of having a unique practice
– he calls himself a “family gastroenterologist”: his major practice consists of kids, but he doesn’t have to say goodbye to them when they’re
18.
What does he like most about his job? Without hesitation, Dr. Howard says it’s about the life stories, which is particularly true in pediatrics. “You get to look after them as kids, and then they grow up and get
married, and now they have kids!” He thoroughly enjoys being part of
people’s lives. This is especially due to his interest in the “doctor-patient
relationship.” Challenging patients are often the ones that stick out in his
mind. He mentions this one tough guy, with bad gastrointestinal disease,
a guy that should have been dead 10 to 15 years ago from complications but still carries on. One night at 5 a.m., Dr. Howard gets a call
from him, finds out that he had lost his son very suddenly, and helps
takes him through it over the phone. Another patient of his with terrible
inflammatory bowel disease has major psychiatric difficulties. He sees
the patient every four to five years, but their entire medical relationship
is on e-mail because the patient has difficulty dealing with face-to-face
communication. “But it’s so interesting,” he remarks, “The patient will
show up at my kid’s performances and just say hi. So I know what the
patient looks like. It’s a wonderful therapeutic relationship – and I don’t
bill anything for it.”
Dr. Howard takes his philosophy of the doctor-patient relationship
directly into the running of his clinic. “I have three kinds of relationships
with patients: positive energy, neutral energy, and negative energy. My
clinics are set up in this way. Most of my encounters are neutral: I’m in
a high energy state, they’re low, I transfer some energy and the patient
feels better and takes up my energy. Positive energy is when I’m high,
they’re low, I see them through the interaction and give them energy but as the relationship develops, they give me energy with their trust and
friendship, and we’re both energized. The bad kind is when I’m high,
they’re low, and I give more energy and it just evaporates – the energy
isn’t transferred.” He says that the key in medicine is to change states:
negative to neutral, and neutral to positive. Just like relationships in life:
some people suck energy from you, most friends are neutral energy, and
some are what you would call love, the traditional positive energy relationship. The positive energy doctor-patient relationship is akin to love
– a professional love.
His secret key to teaching? Seeing the logic in a wrong answer. “If
you’re asking a student what he thinks this patient has, and the patient
has irritable bowel syndrome but the student says Crohn’s disease – you
could just say “No.” Or you could say, “I could see how you might think
that, but this is my perspective.” He likes to acknowledge and see the
logic in a wrong answer – otherwise students just won’t answer. He sees
it as a wonderful academic exercise to see just how that wrong answer
came out. He also likes to be a personal professor, rather than a big
professor. One of the ways he does this is bringing in his own patients
to lecture – an exercise many students consider to be their favourite part
of class. He also learned, though, there is a right and a wrong time to
do it. He used to bring in a patient that had been previously abused by
a physician – right in the first part of medical school. “It was great for
FIFE-ing, but people would get so wrapped up in the case and not look
at the method!” He has now learned to bring in more complicated cases
in second or fourth year – at a level students can come to appreciate.
Dr. Howard’s interest in ecosystem health started with his role in
developing the new medical curriculum: he identified a huge void in the
old curriculum that lacked the topics of health stewardship, advocacy
and public health. After discovering a new ecosystem health program in
Guelph, he realized that public health can be taught to medical students
through ecosystem health. Some of the issues he is working on through
CAPE include: banning the cosmetic use of pesticides, shifting to renewable energy, namely wind power, and elimination of coal generation.
Dr. Howard believes that the environment has a fundamental impact on
our health in a way that most of us are not aware of. Keeping in mind
how our presence alters the environment may be the key in understanding the increasing prevalence of certain diseases. Though it can be challenging to balance his clinical duties and his obligations to CAPE, Dr.
Howard tries to achieve the balanced integration of the two by giving
UWOMJ | 81:2 | Fall 2012
39
PROFILES
grand rounds on ecosystem health, encouraging students to become interested in the field, and being conscious of the impact of his clinical
practice on the environment. He poses the question to his students: are
we doing the right things in medicine, not only for our patients but also
for the environment? “Most people come into medicine with a [sense
of the environment], but they lose it. My job is to maintain it and hopefully stimulate it.” For patients, it comes in their own empowerment.
“People will ask for their kids, ‘So Bob has Crohn’s disease, how do I
prevent the other two from getting it?’ You could say, “Nothing,” which
is very disempowering. But you could tell them instead that there’s this
epidemic of Crohn’s disease – it’s gone up at least 1 log unit since my
starting practice. And I don’t know what that is – but I have to look at
that and live as naturally as possible.”
What does he see for his future? “I’m retiring April 1, 2015!” he says,
with a chuckle. He sees himself as being in a nice part of his career: not
coasting, but having opportunities he can pick for himself. “I can say no
to things because I’m retiring in 3 years!” He says he will probably go
around the world and not be so work-oriented, but then likely will come
back and work in the community in non-invasive gastroenterology. “At
this point in my life, I don’t worry about anyone. A GI bleed doesn’t
bother me, a 1 year old bleeding doesn’t bother me. They used to, but
I’ve seen so many and I won’t be doing those types of cases.” He also
would like to write a book on environmental issues, but doesn’t want to
pressure himself. “People say the bad thing about the environment is –
where do you start? But they have grey coloured glasses on. I have rose
coloured glasses on – and say instead, look at all the opportunities and
different places we can start.”
His advice to medical students: “Remember who you were when you
came into medical school and the values that you had – hold onto them.
Think about creating your own personal mission statement and keep to
it.” His mission statement? “To be a patient centred physician who is
accountable to our community and to deliver that to students.” Many
students struggle with picking a specialty and exactly what they should
do in life. Dr. Howard’s philosophy counters that idea: “Don’t get hung
up on what you’re going to be, but more who you’re going to be.”
40
UWOMJ | 81:2 | Fall 2012
Thinking like an emergency doctor
Elaine Tang (Meds 2015), Roman Shapiro (Meds 2014), Kimberly Fielding (Meds 2014)
Faculty Reviewer: Dr. Naveen Poonai MSc MD FAAP FRCPC (Department of Paediatrics/Internal Medicine)
THE PRESENTING PROBLEM
A previously healthy 14-year-old girl develops acute lower abdominal
pain and vomiting. The pain comes in waves, and the girl is in obvious
distress. Her parents have now brought her to the emergency room.
THE PATIENT’S STORY
The girl had been running and playing soccer with friends outside when
she suddenly had felt a sharp, radiating pain in her abdominal region.
At first, she ignored it and continued playing, but eventually the pain
became so intense that she couldn’t stand. Becoming concerned, her
parents tried to get her to stand, but she was unable to walk. They carried her to the car and drove her straight to the emergency department.
Since the onset of the pain, she began vomiting intermittently. She is
now curled on a stretcher and guarding her stomach.
THE EMERGENCY ROOM
The parents are frantic. Repeatedly, they have demanded that their
daughter be given some form of analgesia or narcotics to control the
pain. The girl’s pain seems to be getting worse. The emergency doctor
works quickly to first assess ABCDE: Airway, Breathing, Circulation,
Disability, and Exposure. Outside of the girl’s pain, it appears that the
girl is stable.
GENERAL APPROACH
The most important thing to determine in children with abdominal pain
is whether this is a life-threatening condition that will require immediate
intervention. If not life-threatening, more time can then be taken to identify the proper cause of the pain.1 There are three areas of examination
that are important:
History – Use the history to try and understand the cause of the abdominal pain. Ask about any trauma to the area, previous surgeries, fever,
vomiting, the location of the pain and pattern of symptoms.21
• Trauma: Abdominal trauma can be life-threatening, especially if
organs are damaged. Remember that for some abdominal injuries,
symptoms may not appear immediately, such as left shoulder pain
from a slowly developing splenic hematoma, or a duodenal hematoma from a lap seatbelt injury.32
• Characteristic of Pain: Obtain information about the onset, frequency, duration, characterization, and location of the pain. Specific diagnoses have particular characteristic patterns of presentation.41
• Associated Symptoms: Signs of fever and abdominal pain are often
correlated with infectious etiologies such as gastroenteritis, viral
syndromes, or pharyngitis. Vomiting in connection with abdominal
pain, especially without diarrhea can be indicative of life-threatening bowel obstruction or appendicitis. Volvulus and intussusception
should also be included on the differential and ruled out, although the
latter is less likely in this age group. A history of a cough should also
be elicited because children with pneumonia frequently complain of
abdominal pain. Lower urinary symptoms should be elicited since
abdominal pain may be a presenting symptom of urinary tract infection (UTI).52 An often missed etiology is a gynecologic emergency
such as ovarian torsion, ectopic pregnancy, etc., necessitating a complete gynecological history.63
• Past Medical History: Previous abdominal surgeries, UTIs and preexisting conditions such as Sickle Cell Disease should be taken into
consideration.72
Physical examination – Vital signs and detailed abdominal examination are essential.81
• Appearance: Look at the patient
• Hypovolemia can be indicative of abdominal injury, volvulus, or
intussusceptions
• Jaundice can indicate hepatitis or hemolysis
• Vital Signs: Key features to keep in mind are fever, which would
suggest an infection, tachypnea, which may indicate respiratory illness or metabolic acidosis, and hypotension, which can develop from
intravascular volume loss or peritonitis.
• Abdominal Examination: Look for distention, listen for bowel
sounds, localize quadrant pain, and percuss for tenderness, rebound,
or involuntary guarding. Rectal exam may be indicated, and stools
should be observed for softness and blood.
• General Examination: Extra-abdominal findings can help determine
the cause of abdominal pain, such as respiratory symptoms suggestive of pneumonia, altered heart sounds indicating either pericarditis
or myocarditis, flank tenderness suggestive of pyelonephritis or urolithiasis, or rashes/bruises indicative of Henoch-Schonlein purpura.92
For sexually active females with lower abdominal pain, bimanual
pelvic examinations should be done to look for pelvic inflammatory
disease, adnexal masses or cysts, uterine pathologies, etc.103 The costovertebral angle should also be percussed.
Ancillary studies – Laboratory and radiographic testing should only be
done if there are focal concerns that suggest a particular diagnosis that
can be confirmed with imaging/lab testing.
• Laboratory Test: WBC, hematocrit, serum chemistries, urine dipstick, urine pregnancy test, rapid Streptococcal antigen testing, etc.
• Imaging: Plain radiography, ultrasound, CT scan
• FAST: Focused abdominal sonography for trauma – performed in
the emergency room to quickly determine free fluid in the abdo-
UWOMJ | 81:2 | Fall 2012
41
men.111
• ECG: Can assess voltage, ST changes and T wave abnormalities that
can suggest pericardial disease
ANALGESIC USE
Children with acute abdominal pain should receive an effective analgesic based on their level of discomfort.121 While there have been concerns
about the use of analgesics altering the accuracy of clinical findings,
clinical trials have shown that morphine analgesic use in children with
acute abdominal pain is able to provide pain relief without significantly
changing clinical examinations or determination of surgical conditions.
NSAIDs are also acceptable for pain control. Despite the presence of
this data, current observational studies indicate that children often do not
receive adequate pain control in these acute circumstances.131
THE SPECIALIST EXAM
In a debriefing by the parents, the emergency doctor conducted a quick
test to rule out potential life-threatening causes of the girl’s pain. When
making a secondary survey, think AMPLE: allergies, medications, past
illnesses, last meal, and events preceding the injury.
History – The parents did not report any significant trauma incurred
during the soccer game. Other than the lower abdominal pain, the girl is
not complaining of discomfort anywhere else. She is localizing the pain
to her right lower abdominal quadrant and radiating to her back. She
describes the pain to be sharp and stabbing. She also reports other recent “stomach pains” that resolved spontaneously, believing these pains
may have been due to menstrual cramping. She has no previous medical
conditions. She is currently experiencing some nausea, and has vomited
twice in the last few hours.144
tion of diagnosis and treatment, usually on an in-patient basis. Prompt
diagnosis and timely management help save the adnexal structures from
infarction and facilitate a speedy recovery.204
REFERENCES
1. Neuman MI, Ruddy RM, Fleisher GR, Ferry GD, Drutz JE, Wiley JF. Emergent evaluation of the child with acute abdominal pain. [Internet]. UpToDate;
2012 Apr 13 [updated 2012 Apr 13; cited 2012 May 27]. Available from:
http://www.uptodate.com/contents/emergent-evaluation-of-the-child-withacute-abdominal-pain?source=search_result&search=ovarian+torsion&selec
tedTitle=8~32
2. Ferry GD, Fleisher GR, Drutz JE, Wiley JF. Causes of acute abdominal pain
in children and adolescents [Internet]. UpToDate; 2010 Aug 31; [updated
2010 Aug 31; cited 2012 May 27]. Available from: http://www.uptodate.
com.proxy1.lib.uwo.ca:2048/contents/causes-of-acute-abdominal-pain-inchildren-and-adolescents?source=search_result&search=pediatric+acute+ab
dominal+pain&selectedTitle=1~150
3. Brown K, Lee JA, Teach SJ, Wiley JF. Evaluation of acute pelvic pain in
the adolescent female. [Internet]. UpToDate; 2011 Feb 8 [updated 2011 Feb
8; cited 2012 May 27]. Available from: http://www.uptodate.com/contents/
evaluation-of-acute-pelvic-pain-in-the-adolescent-female?source=search_res
ult&search=ovarian+torsion&selectedTitle=2~32
4. Growdon WB, Laufer MR, Mann WJ, Falk SJ. Ovarian and fallopian tube
fusion. [Internet]. UpToDate; 2011 Jun 2 [updated 2011 Jun 2; cited 2012
May 27]. Available from: http://www.uptodate.com/contents/ovarian-andfallopian-tube-torsion?source=search_result&search=ovarian+torsion&selec
tedTitle=1~32
Physical examination – The patient does not appear to be hypovolemic or jaundiced. She has a unilateral, tender adnexal mass with some
tenderness to palpation. There are no other remarkable findings. Stool
samples have been normal.154
Ancillary studies – Blood is drawn and a CBC shows normal levels of
WBC and hematocrit. β-HCG levels are ordered, and the results are not
suggestive of an ectopic pregnancy. Since she has lower abdominal pain,
it was decided that a pelvic ultrasound would be carried out. Results
showed an enlarged ovary to one side, with multiple small immature
follicles along the periphery.164 Concerned about cysts, cancer, or other
pathologies, a color Doppler U/S and CT scan were performed to show
morphological and physiological changes in the ovary, and to assess
blood flow. Very little intraovarian venous flow was present.174
SOLVING THE MYSTERY
After taking a detailed history and imaging, the diagnosis of ovarian torsion was made with the help of a gynecologic consult.184 The presence
of an enlarged ovary with a decrease in intraovarian venous flow alerted
physicians this diagnosis. Laparoscopic surgery was quickly booked. In
the meantime, morphine was used to control the girl’s pain until she was
able to go to the OR.
CONCLUDING REMARKS
Ovarian torsion can easily mimic other GI causes of acute abdominal
pain such as constipation, bowel obstruction, appendicitis, intussusceptions, gastroenteritis, renal colic, ans mesenteric adenitis.194 Despite its
rarity in presentation, ovarian torsion should still be on the differential
diagnosis when females present with severe, acute, lower abdominal
pain. Due to its variable presentation and often non-specific findings,
the diagnosis of ovarian torsion is often missed and ramifications for the
delay can result in a necrotic ovary. Laparoscopy is used for confirma-
42
UWOMJ | 81:2 | Fall 2012
ZEBRA FILES
A case of adult intussusception: a curious
presentation
Yikang Lin (Meds 2014), Stephen Cornish (Meds 2015)
Faculty Reviewer: Dr. Patrick Colquhoun, MD (Department of General Surgery)
I
t is well established that a diagnosis can be made solely on the basis
of a patient’s history in the majority of cases. Physical examination
may reveal more clues to the patient’s complaint, diagnostic tests are
used to identify, assess, and confirm any physiological basis for disease.
However, a thorough history and good clinical acumen contribute most
to a medical diagnosis and treatment selection. This daunting idea is
also reassuring, in that there is no substitute for a sound diagnostic approach that one can gain from experience. There is, however, always
opportunity for a rare occurrence, a peculiar presentation, a proverbial
‘zebra’ to slip past our detection despite our most diligent efforts. Disguised by common or vague symptoms rather than stripes, these ‘zebras’
are a chance to step outside of the usual diagnostic process, summon a
protracted differential diagnosis from our training, and regard an unsolved medical problem with new eyes. When the patterns of everyday
medicine are broken by such a case, the importance of an astute doctor
is starkly illuminated.
The following case was described by Yalamarthi and Smith.1 A 42
year old male with a three day history of melena presented to his general practitioner, who referred the patient for consultation. He had been
previously investigated for iron deficiency anemia, with no cause having
been identified. At the time of consult, the patient’s haemoglobin was
low (86 g/L) and was suggestive of an iron deficiency etiology. The initial investigation that was performed was an upper GI endoscopy, which
revealed minimal esophagitis. The absence of significant esophagitis is
of interest because iron deficiency has been known to coincide with both
hiatal hernias and esophagitis.2 The patient elected for a conservative
investigative approach and underwent a normal barium enema.
Since this patient’s initial presenting complaint was an acute history
of melena, it may be helpful to review the differential diagnostic thought
process that would be triggered by this symptom. Melena refers to black,
tarry stool caused by the presence of blood. The tarry appearance is created by the digestion of red blood cells and their contents (specifically
the oxidation of iron in hemoglobin) by the activity of the GI tract as it
passes through the intestine and colon.3 For the blood to be digested in
this way, its source must originate early in the gastrointestinal tract; this
fact allows physicians to classify a GI bleed as being an ‘upper GI bleed’
by the presence of melena. About 90% of melena originates proximal
to the ligament of Treitz (a structural support connecting the duodenum
to the diaphragm), but some cases can originate in the small intestine
or proximal colon.4 Conversely, the presence of bright red blood in the
stool is indicative of a ‘lower GI bleed’, from the distal colon or rectum.
This distinction can be very helpful in pursuing a diagnosis.
Causes of upper GI bleed can vary greatly, and a detailed history
is critical to ruling in or ruling out these potential situations. Potential bleeding causes in the upper GI tract include peptic ulcer disease,
esophageal varices, portal hypertensive gastropathy, malignancies, an-
giodysplasia, and aorto-enteric fistula.5 Peptic ulcer disease is a common cause of upper GI bleeding, and is seen in patients with a history
of Helicobacter pylori infection. Marginal or anastomotic ulcers can be
present in patients with gastroenteric anastomosis. Esophageal varices
and portal hypertensive gastropathy can be seen in patients who have a
history of alcohol abuse or liver disease. Malignancies can occur in the
upper GI tract in patients with a history of smoking, alcohol abuse, or
bacterial infections such as Helicobacter pylori. In patients with renal
disease, aortic stenosis, or hereditary hemorrhagic telectasia, resultant
angiodysplasia can lead to bleeding in the upper GI structures. Finally, an aorto-enteric fistula can develop in patients who have a history
of aortic aneurysm or an aortic graft. An assessment of medications
is also necessary to determine if there may be a pharmacological basis
for the upper GI bleed, which can be seen in the following situations:
non-steroidal anti-inflammatory drugs leading to peptic ulcer disease,
irritation of the esophagus by medications leading to pill esophagitis,
anti-coagulants which promote bleeding, and bismuth or iron which can
give stool the appearance of melena without causing a bleed.5
The patient was seen again in clinic, and upon this second visit he
complained of left upper quadrant pain.1 He was still anemic at this
time, with a haemoglobin of 98 g/L, despite being advised to take iron
supplements after his first consultation. There were no signs of overt
blood loss, and no apparent clues to suggest a hidden source. A barium
meal follow through showed distortion of the terminal ileum, which was
initially assessed as extrinsic compression of the intestine by the sigmoid colon. Further investigation using computed tomography (CT)
showed an abnormally thickened region of the ileum. On the scan, this
region had a target-like appearance as well as intra-luminal fat present, a
finding consistent with our gastrointestinal ‘zebra’ condition.
Our patient’s first investigations were barium studies. The contents
of the GI tract are difficult to discern on an X-Ray, so barium salts,
which are non-toxic radio-opaque, are inserted to help with visualization. The first test performed was a barium enema, which investigates
the colon. After a patient empties their colon, a well-lubricated enema
tube is inserted into the patient’s rectum. The colon can be filled with
barium alone – a “single contrast” barium enema - or barium followed
by air – a “double-contrast” barium enema.6 X-Ray fluoroscopy reveals
details about the intestinal lumen and mucosa, with double-contrast
barium enemas providing better information on the lining. Our patient’s
lesion was located above the range visible via a barium enema. The second investigation, a barium meal, is a similar process that investigates
foregut structures instead of the colon.7 This investigation revealed a
compression of the terminal ileum. With CT imaging, hallmark signs of
an intussusception were visualized, specifically a target-shaped appearance indicating overlapping bowel walls, and intra-luminal fat, which
indicates entrapped mesenteric fat.1
UWOMJ | 81:2 | Fall 2012
43
ZEBRA FILES
An intussusception is the telescoping of one segment of bowel into
an immediately adjacent segment of bowel.8 It is found far more commonly in pediatric populations (95% of all intussusception cases are in
children), and accounts for less than 5% of adult cases of gastrointestinal
obstruction. In children, it is almost always benign and idiopathic, and
resolves with the barium enema that is used to diagnose it – the hydrostatic pressure of barium fluid - with or without air - will cause the telescoped bowel to reduce into anatomical position.9 Furthermore, children
often present with the classic triad of intussusception symptoms: vomiting, rectal bleeding, and abdominal pain. In adults, intussusception often
presents with vague abdominal symptoms, which a careful clinician may
be able to discern. Abdominal pain associated with intussusception is
generally periodic and intermittent, and is sometimes accompanied by
blood in vomit and/or stool.10 Furthermore, intussusceptions in adults
are rarely idiopathic, with malignant growths accounting for 6-30% of
adult intussusception cases, and majority occurring from benign pathology. Our patient had a traumatic ulcer in a Meckel’s diverticulum that
served as the lead point for the telescoping to occur.
Meckel’s diverticulum is a congenital anomaly of the small bowel,
occurring in 2% of the population, and more commonly seen in males
than females.11 If it is present in an individual, it is usually found within
two feet of the ileocecal valve. This vestigial structure represents an incomplete closure of the omphalomesenteric or vitelline duct, which connects the midgut of the developing embryo to the yolk sac while in utero.
A Meckel’s diverticulum is typically asymptomatic, with only 2% of
cases actually developing any complications over their lifetime. As was
seen in our patient, bleeding from the diverticulum is painless, and can
result from mucosal ulceration within ectopic gastric tissue. This ectopic tissue can continue to produce secretions that are characteristic of
the tissue’s embryological origin, such as acid and protease-containing
digestive fluid. These secretions can gradually break down the mucosal
lining of the diverticulum causing ulceration and bleeding.
The finding of melena in this case was curious because the Meckel’s
diverticulum was located in the distal ileum. As was previously mentioned, gastro-intestinal bleeding from the lower digestive tract (distal
to the ligament of Treitz in the duodenum) would normally present as
bright red blood in the stool. The approach presented by Cappell and
Friedel for the evaluation of acute upper gastrointestinal bleeding states
that some cases of melena can arise from pathology in the distal small
bowel and even the proximal colon.4 With this in mind, this case truly
was atypical: an uncommon presentation of an unusual pathology.
REFERENCES
1. Yalamarthi S, Smith RC. Adult intussusception: case reports and review of
the literature. Postgraduate Medical Journal 2005; 81:174-177.
2. Ruhl CE, Everhart JE. Relationship of iron deficiency anemia with esophagitis and hiatal hernia: hospital findings from a prospective, population-based
study. American Journal of Gastroenterology 2001; 96:322-326.
3. Srygley FD, Gerardo CJ, Tran T, Fisher DA. Does this patient have a severe
upper gastrointestinal bleed? Journal of the American Medical Association
2012; 307:1072-1079.
4. Cappell MS, Friedel D. Initial management of acute upper gastrointestinal bleeding: from initial evaluation up to gastrointestinal endoscopy.
Medical Clinics of North America 2008; 92:491.
5. Dallal HJ, Palmer KR. ABC of the upper gastrointestinal tract: upper gastrointestinal hemorrhage. British Medical Journal 2001; 323:1115-1117.
6. Wan A, Darzi A. Investigation of colonic disease. Hospital Medicine 2000;
61:692-697.
7. Levine MS. Role of the double-contrast upper gastrointestinal series in the
1990s. Gastroenterology Clinics of North America. 1995; 24:289-308.
8. Loukas M, Pellerin M, Kimball Z, de la Garza-Jordan J, Tubbs RS, Jordan
R. Intussusception: an anatomical perspective with review of the literature.
Clinical Anatomy 2011; 24:552-561.
9. Buettcher M, Baer G, Bonhoeffer J, Schaad UB, Heininger U. Three-year
surveillance of intussusception in children in Switzerland. Pediatrics 2007;
120:473-480.
10.Gayer G, Zissin R, Apter S, Papa M, Hertz M. Pictorial review: adult intussusception – a CT diagnosis. British Journal of Radiology 2002; 75:185-190.
11.Uppal K, Tubbs RS, Matusz P, Shaffer K, Loukas M. Meckel’s diverticulum:
a review. Clinical Anatomy 2011; 24:416-422.
12.Marinis A, Yiallourou A, Samanides L, Dafnios N, Anastasopoulos G, Vassiliou I, Theodosopoulos T. Intussusception of the bowel in adults: a review.
World Journal of Gastroenterology 2009; 15:407-411.
There are generally two options in treatment – resection of the involved bowel sections, or reduction – i.e. returning the bowel to anatomical position. Generally, pediatric cases of intussusception will be resolved via reduction of the telescoping regions, with the option to resect
the affected region if it is irreparably damaged.12 In adult patients, due
to the high prevalence of malignant tumors and the associated risk of
dissemination if reduction is attempted, the preference is for resection.
Colo-anal intussusceptions are the notable exception, as reducing could
spare the anal sphincter, which is needed to retain bowel continence, as
well as post-traumatic and idiopathic intussusceptions in which the risk
of malignancy is insignificant.
Our patient underwent a laparoscopic procedure under general anesthetic to resect a section of his small bowel.1 Depending on the amount
of healthy bowel left after resection, the remaining bowel can be reconnected, or an ileostomy can be performed in which remaining bowel
is directed through an opening in the abdomen to a drainage bag. Our
patient had approximately 1 foot of bowel removed, thus his remaining
bowel segments were reattached. He made an uneventful post-operative
stay and made a full recovery to normal bowel function.
44
UWOMJ | 81:2 | Fall 2012
HISTORY OF MEDICINE
Helicobacter pylori: hiding in the modern miasma
Justine Denomme (Meds 2015) and Jason L. Chan (MD/PhD 2017)
Faculty Reviewer: Dr. Carole Creuzenet, PhD (Department of Microbiology and Immunology)
W
hen Ignaz Semmelweis proposed and demonstrated that handwashing would decrease the incidence of puerperal fever in
the mid-nineteenth century, he was ignored, criticized, and
ridiculed. Miasma, or bad air, was believed since ancient times to cause
disease, and consequently, hand-washing had no place in medical care.
Of course, this is no longer the case, but decades passed before Semmelweis’ recommendations gained widespread acceptance. His discovery
was controversial and met with resistance. Eventually, the germ theory
of disease replaced the miasma theory, and Koch’s postulates provided
a concrete method to establish a causal relationship between a microorganism and a disease. Despite the struggles of earlier researchers and
clinicians to advance medicine, resistance to new knowledge and discoveries still prevails. The story of the bacterium Helicobacter pylori
provides a modern example of this resistance.
Today, when a person is diagnosed with peptic ulcer disease (PUD)
and an H. pylori
infection, they are promptly treated with a brief course of two antibiotics.1 Elimination of the bacterial infection is associated with more
rapid healing of ulcers and reduces the risk of relapse.1 The association between bacterial infection and peptic ulcers was discussed within
scientific literature as early as the late 19th century but a definitive link
between peptic ulcer disease and specific bacteria was not established
until 1984.2 Furthermore, in 1995, a study of treatment patterns of peptic
ulcer disease in the United States showed that only 5% of patients were
being treated with antibiotics in order to eradicate H. pylori.3 Why did
this happen? Firstly, the characteristics of H. pylori made it difficult to
study. Secondly, there was already a well-established theory regarding
the etiology of peptic ulcers when the bacteria were first successfully
cultured. Finally, the medical community was more hesitant than the
scientific community to accept infection as causative of peptic ulcers.
Unlike many other disease-causing bacteria, H. pylori did not easily
fulfill Koch’s postulates for peptic ulcer disease. The second postulate
states that a disease-causing microorganism must be isolated and grown
in pure culture.4 With the advent of microscopy and germ theory, early
bacteriologists and pathologists identified bacterial colonies associated
with ulcer tissue samples on several occasions.5 However, H. pylori was
not successfully cultured until 1982, by Drs. Barry Marshall and Robin
Warren.2 The bacteria are especially difficult to culture even today because they grow 10 to 15 times more slowly than Escherichia coli, are
microaerophilic, and require specific culture media. Interestingly, Marshall and Warren’s early experiments were only successful when a plate
that was accidentally left over the Easter weekend instead of being discarded after 48 hours without growth grew colonies.2
Furthermore, Koch’s third postulate states that disease should be reproduced when the cultured microorganism is introduced into a healthy,
susceptible host.4 This postulate was memorably proven by Dr. Barry
Marshall when he ingested a culture of H. pylori isolated from a patient
with gastritis.6 This was the only way to fulfill Koch’s third postulate
at the time because most H. pylori strains only infect humans.6 This
proved to be problematic for early animal studies on gastritis. Bacteria
associated with inflamed gastric mucosa of rhesus monkeys and with
human gastric tissue was studied by J.L. Doenges in 1938 and later by
Freedberg and Barron in 1941.5 Unfortunately, the bacteria from rhesus
monkeys were histologically different from those in humans and bacteria were more difficult to identify in human tissue samples. Therefore,
it could not be definitively concluded that bacteria caused gastric inflammation.5 Later, when Dr. Marshall initially attempted to implement
Koch’s third postulate, he unsuccessfully attempted to transfer H. pylori
cultures to piglets.7 It was only more recently that more suitable animal
models were developed.8,9 Fulfilling Koch’s postulates in the case of H.
pylori was more difficult than for many other types of bacteria. These
characteristics of H. pylori delayed the development of efficient methods for its study can partially explain why it was not easily established
as one of the causes of peptic ulcer disease.
Although identifying H. pylori was difficult, once Marshall and Warren presented their findings to the world, other microbiologists verified
and accepted them. However, gastroenterologists were more reluctant
to accept this new information. Eventually, Drs. Marshall and Warren’s
work became formally recognized when they were awarded the Nobel
Prize in Physiology or Medicine in 2005. In his Nobel Lecture, Dr. Marshall stated that the greatest obstacle to his work was that the cause of
peptic ulcer disease was “already known”.10 When Warren and Marshall
isolated and cultured H. pylori, H2 receptor antagonists were an established treatment for peptic ulcer disease.11 The use of these drugs, which
decreased acid secretion in the stomach, helped validate a theory of the
etiology of peptic ulcer disease at the time: the stomach was secreting
too much acid or the mucosal lining was less resistant to stomach acid,
causing damage, ulcers, and pain. It was thought that intrinsic factors
such as psychological stress or habits such as smoking made the stomach lining more vulnerable to damage.11 In the case of ulcers caused by
H. pylori, is suggested that it is mainly the bacterial infection which
results in increased acid secretion due to the body’s reaction to the infection.12 Another predominant theory was that the stomach was too acidic
for bacteria to grow.11 Therefore, when bacteria were historically observed on samples of gastric tissue, they were thought to be artefacts.5
Based on what had been traditionally taught in medical schools at the
time of the discovery of H. pylori, Drs. Marshall and Warren’s research
would have been very extraordinary.
There are several others reasons why the medical community did not
eagerly embrace Marshall and Warren’s findings. To begin, testing for
H. pylori was originally invasive and inaccurate and physicians did not
UWOMJ | 81:2 | Fall 2012
45
HISTORY OF MEDICINE
want to treat people with antibiotics unnecessarily for fear of antibiotic
resistance.13,14 Secondly, throughout the 1980s, the pharmaceutical industry continued to pursue the development of treatments that did not
account for a bacterial etiology of PUD.15 In 1988, proton pump inhibitors, such as omeprazole, were launched as an alternative to H2-antagonists.15 The pharmaceutical company producing omeprazole organized
an international symposium on PUD that year, featuring 33 notable gastroenterologists, yet only one of the 67 posters and abstracts presented
dealt with H. pylori.15 Finally, continuing medical education may not
have been as effective at keeping physicians aware of changes in medical practices in the past as it is today.16 It was traditionally based on selfdirected learning and self-assessment, which could lead to deficiencies
in medical knowledge and a lack of accountability.16 In addition, some
continuing medical education has historically been funded by the pharmaceutical industry, which could potentially introduce bias into the curriculum.17 Accepting new theories that challenge previously-established
beliefs can be very difficult. In this case, the lack of resources and information likely contributed to the delay in eradication of H. pylori becoming the standard of patient care for gastritis and PUD.
One of the most important factors in the acceptance of the eradication of H. pylori from the stomachs of symptomatic patients was the
discovery that H. pylori is carcinogenic.18 Research into the relationship
of H. pylori and certain cancers began shortly after its discovery and
by 1994 the International Agency for Research on Cancer reviewed the
available literature and concluded that people infected with H. pylori
are at increased risk for developing gastric adenocarcinoma and gastric
B-cell mucosa-associated lymphoid tissue (MALT) lymphoma.18 Gastric adenocarcinoma is a leading cause of cancer death worldwide and
is typically associated with a poor prognosis.19,20 Interestingly, MALT
lymphoma can be treated by eradication of H. pylori and it has been
suggested that H. pylori eradication could help prevent future gastric
cancer.21 Cancer is one of the most notorious diseases in our society,
and the association of H. pylori infection with malignant disease was
further evidence to support that an H. pylori infection requires medical
attention.
The journey towards establishing an etiology for peptic ulcer disease
was long and exceedingly difficult. H. pylori possesses many characteristics that make it difficult to culture and establish a cause-and-effect
relationship with peptic ulcer disease. Furthermore, the idea was unappealing to many because it challenged previously established views
and challenged physicians to revisit traditional medical knowledge. In
order to truly provide the best possible care to patients, physicians must
embrace the dynamic, surprising, and ever-changing aspects of the field
of medicine. With improved continuing medical education and with improved access to medical journals online, this has never been more possible. Many fields of medical science, including Helicobacter pylori, are
still active areas of research locally and globally and emerging knowledge will certainly continue to challenge physicians to improve medical
practices in the future.
dent and Fellows of Harvard College. 2012. [cited 2012 May 3]. Available
from: http://ocp.hul.harvard.edu/contagion/koch.html
5. Kidd M, Modlin IM. A century of Helicobacter pylori: paradigms lost-paradigms regained. Digestion. 1998;59(1):1-15.
6. Hellström PM. Spotlight on gastroenterology - the Nobel Prize Laureates in
Physiology or Medicine 2005: John Robin Warren and Barry James Marshall.
Scand J Gastroenterol. 2005 Dec;40(12):1383-5.
7. Marshall B. Helicobacter connections. ChemMedChem. 2006 Aug;1(8):783802.
8. Marchetti M, Aricò B, Burroni D, Figura N, Rappuoli R, Ghiara P. Development of a mouse model of Helicobacter pylori infection that mimics human
disease. Science. 1995 Mar 17;267(5204):1655-8.
9. Oshio I, Osaki T, Hanawa T, Yonezawa H, Zaman C, Kurata S, Kamiya S.
Vertical Helicobacter pylori transmission from Mongolian gerbil mothers to
pups. J Med Microbiol. 2009 May;58(Pt 5):656-62.
10.Marshall B. Helicobacter connections. ChemMedChem. 2006 Aug;1(8):783802.
11.Yeomans ND. The ulcer sleuths: The search for the cause of peptic ulcers. J
Gastroenterol Hepatol. 2011 Jan;26 Suppl 1:35-41.
12.Calam J, Gibbons A, Healey ZV, Bliss P, Arebi N. How does Helicobacter
pylori cause mucosal damage? Its effect on acid and gastrin physiology. Gastroenterology. 1997 Dec;113(6 Suppl):S43-9; discussion S50.
13.Cutler AF, Havstad S, Ma CK, Blaser MJ, Perez-Perez GI, Schubert TT. Accuracy of invasive and noninvasive tests to diagnose Helicobacter pylori infection. Gastroenterology. 1995 Jul;109(1):136-41.
14.Neu HC. The crisis in antibiotic resistance. Science. 1992 Aug
21;257(5073):1064-73.
15.Ciacci C, Mazzacca G. The history of Helicobacter pylori: a reflection on the
relationship between the medical community and industry. Dig Liver Dis.
2006 Oct;38(10):778-80. Epub 2006 Jul 25.
16.Norman GR, Shannon SI, Marrin ML. The need for needs assessment in continuing medical education. BMJ. 2004 Apr 24;328(7446):999-1001.
17.Marlow B. The future sponsorship of CME in Canada: industry, government,
physicians or a blend? CMAJ. 2005 Jan 18;172(2):160-2.
18.IARC working group on the evaluation of carcinogenic risks to humans.
Schistosomes, liver flukes, and Helicobacter pylori. Lyon, June 7 to 14, 1994.
IARC Monogr Eval Carcinog Risks Hum. 1994;61:1-241.
19.Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin.
2012 Jan-Feb;62(1):10-29.
20.Stomach cancer; 5-year survival statistics by stage [Internet]. American Cancer Society. 2012 [cited 2012 May 18]. Available from: http://www.cancer.
org/Cancer/StomachCancer/DetailedGuide/stomach-cancer-survival-rates
21.Fischbach W, Goebeler-Kolve ME, Dragosics B, Greiner A, Stolte M. Long
term outcome of patients with gastric marginal zone B cell lymphoma of mucosa associated lymphoid tissue (MALT) following exclusive Helicobacter
pylori eradication therapy: experience from a largeprospective series. Gut.
2004 Jan;53(1):34-7.
REFERENCES
1. Leodolter A, Kulig M, Brasch H, Meyer-Sabellek W, Willich SN, Malfertheiner P. A meta-analysis comparing eradication, healing and relapse rates
in patients with Helicobacter pylori-associated gastric or duodenal ulcer. Aliment Pharmacol Ther. 2001 Dec;15(12):1949-58.
2. Marshall BJ, Warren RJ. Unidentified curved bacilli in the stomach of patients
with gastritis and peptic ulceraction. Lancet. 1984 Jun 16;1(8390):1311-5.
3. Munnangi S, Sonnenberg A. Time trends of physician visits and treatment
patterns of peptic ulcer disease in the United States. Arch Intern Med. 1997
Jul 14;157(13):1489-94.
4. Contagion: Historical Views of Diseases and Epidemics [Internet]. The Presi-
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